Antibodies for IL-17C

ABSTRACT

The present invention provides antibodies or antibody fragments binding to human IL-17C. In particular, it relates to antibodies or antibody fragments that have combined beneficial properties and are therefore useful for the treatment of humans having, for example, atopic dermatitis or psoriasis.

FIELD OF THE INVENTION

The present application relates to antibodies or antibody fragmentswhich interact with human IL-17C. The invention also relates to nucleicacids, vectors and host cells capable of expressing said antibodies orfragments thereof, pharmaceutical compositions comprising saidantibodies or fragments thereof and uses of said antibodies or fragmentsthereof for the treatment of specific diseases.

BACKGROUND

IL-17C is a secreted homodimer of the IL17 protein family. In vitro ithas been shown that IL-17C stimulates the release of TNF-α and IL-β fromthe monocytic cell line THP-1 (Li et al. (2000) Proc. Natl. Acad. Sci.U.S.A. 97, 773-8). IL-17C can induce the mRNA expression of inflammatorycytokines such as IL-1β, IL-6 and IL-23 in peritoneal exudates cells(PECS) and the 3T3 cell line (Yamaguchi et al. (2007) J. Immunol 179,7128-36).

The role of IL-17C as a proinflammatory cytokine relevant for hostdefense was postulated in several studies (Chang et al. (2011) Immunity35, 611-621, Song et al. (2011) Nature Immunology 12, 12,Ramirez-Carrozzi et al. (2011) Nature Immunology 12, 12). Also apotential role in the progression of specific tumours and canceroustissues was recently shown (Xinyang Song (2014) Immunity 40, 140-152).

Recently in WO 2013/057241 it was experimentally evaluated thatinhibition of IL-17C is a promising approach to treat inflammatorydisorders. However, respective antibodies used in WO 2013/057241 weresurrogate antibodies specific for mouse IL-17C, but were shown not to bereactive to human IL-17C at all. In addition, further antibodies thatantagonize IL-17C were already suggested (e.g. in WO 1999/060127), butare either polyclonal sera or surrogate antibodies which specificallybind to mouse IL-17C only.

Accordingly, a need exists to study and identify antibodies that bind tohuman IL-17C to ameliorate IL-17C related diseases or disorders inhuman.

SUMMARY OF THE INVENTION

The present disclosure provides novel antibodies and antibody fragments.The antibodies and antibody fragments disclosed herein bind to humanIL-17C and also cross-react with IL-17C from the cynomolgus monkey andthe mouse. In addition the disclosed antibodies inhibit binding ofIL-17C to its receptor throughout the relevant species—human, mouse andcynomolgus monkey—with an IC₅₀ concentration of 80 pM or less. Asdisclosed and exemplified herein, said antibodies proved to be effectivein various in vivo mouse models for atopic dermatitis and psoriasis.

Thus, the disclosed antibodies or antibody fragments are superior interms of effectiveness and provide well suited and promising compoundsfor the treatment of humans having, for example, atopic dermatitis orpsoriasis.

The present disclosure provides antibodies or antibody fragments thatbind to human IL-17C having CDR regions according to Table 1 of thepresent specification. The present disclosure also provides specificantibodies or antibody fragments having a variable heavy chain regionand a variable light chain CDR regions comprising the amino acidsequences according to Table 1 of the present specification.

The present disclosure also provides specific antibodies or antibodyfragments which compete with the specific antibodies or antibodyfragments disclosed herein. The present disclosure also providesspecific antibodies or antibody fragments which bind to the same epitopeas the specific antibodies or antibody fragments disclosed herein.

The present disclosure also provides the isolated antibodies or antibodyfragments of the present disclosure for use in medicine.

The present disclosure also provides also provides methods for treatinga subject suffering from a disorder, such as an inflammatory disorder,by administering to said subject an effective amount of the antibodiesor antibody fragments of the present disclosure. Preferably said subjectis a human.

The present disclosure also provides pharmaceutical compositionscomprising the isolated antibodies or antibody fragments of the presentdisclosure, and a pharmaceutically acceptable carrier.

The present disclosure also provides nucleic acids encoding theantibodies or antibody fragments of the present disclosure.

The present disclosure also provides vectors comprising nucleic acidsencoding the antibodies or antibody fragment antibodies of the presentdisclosure.

The present disclosure also provides host cell comprising vector ornucleic acids encoding the antibodies or antibody fragments of thepresent disclosure.

There is utility in the claimed antibodies or antibody fragments.Furthermore, there is utility in the claimed method to identify suchantibodies or fragments.

Utilization of the claimed antibodies or antibody fragments is to alterthe biological activity of human IL-17C. In particular the claimedantibodies or antibody fragments are for therapeutic use, such as thetreatment of inflammatory disorders like e.g. rheumatoid arthritis,psoriasis, pulmonary inflammation, COPD and/or the treatment of atopicdermatitis (AD), including moderate-to-severe AD.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: MAB #1 dose-dependently prevents the ear thickening induced bytopical application of MC903 on ear skin.

Data are expressed as mean values±standard error of the mean (SEM) (n=8per group). Statistical significance versus MC903+MOR03207 wascalculated using ANOVA and Dunnett's multiple comparison test: *p<0.05;**p<0.01; ***p<0.001. (DEX: dexamethasone; EtOH: ethanol)

FIG. 2: MAB #1 dose-dependently reduces the ear inflammation induced bytopical application of MC903 on ear skin.

Ear inflammation was assessed at Day 5 using in vivo imaging. Leftpanel: quantification of signal intensity in ears. Individual datapoints (n=8 per group) represent the average intensity of both ears;data are also shown as mean values (horizontal lines)±SEM. Statisticalsignificance versus MC903+MOR03207 was calculated using ANOVA andDunnett's multiple comparison test: *p<0.05; **p<0.01; ***p<0.001. Rightpanel: representative images of mouse ears from animals from differenttreatment groups were acquired on the Bruker In-vivo Xtreme Imager 24 hafter injection of the Prosense 680 probe. (DEX: dexamethasone; EtOH:ethanol)

FIG. 3: MAB #1 dose-dependently reduces the thickening of epidermal anddermal skin layer induced by topical application of MC903 on ear skin.

Data are presented as individual data points (n=8 per group) and meanvalues (horizontal lines)±SEM. Statistical significance versusMC903+MOR03207 was calculated using ANOVA and Dunnett's multiplecomparison test: *p<0.05; **p<0.01; ***p<0.001. Left panel: data forepidermal thickness; Right panel: data for dermal thickness.

FIG. 4: MAB #1 dose-dependently inhibits the MC903-mediated increase inTSLP and IL-33 expression in ear and TARC levels in plasma.

Data are presented as individual data points (n=8 per group) and meanvalues (horizontal lines)±SEM. Statistical significance versusMC903+MOR03207 group was calculated using ANOVA and Dunnett's multiplecomparison test: *p<0.05; **p<0.01; ***p<0.001. Top left panel: data forTSLP protein expression in ear; Bottom left panel: data for IL-33protein expression in ear; Top right panel: data for TARO protein levelsin plasma.

FIG. 5: Therapeutic administration of MAB #1 dose-dependently reducesthe ear thickening induced by topical application of MC903 on ear skin.

Data are expressed as mean values±SEM (n=10 per group). Statisticalsignificance versus MC903+MOR03207 was calculated using ANOVA andDunnett's multiple comparison test: * p<0.05; **p<0.01; ***p<0.001. DEX:dexamethasone; EtOH: ethanol.

FIG. 6: Therapeutic administration of MAB #1 dose-dependently reducesthe ear inflammation induced by topical application of MC903 on earskin.

Ear inflammation was assessed at Day 12 using in vivo imaging and thesignal intensity in ears is graphically represented. Individual datapoints (n=10 per group) represent the average intensity of both ears;data are also shown as mean values (horizontal lines)±SEM. Statisticalsignificance versus MC903+MOR03207 was calculated using ANOVA andDunnett's multiple comparison test: *p<0.05; **p<0.01; ***p<0.001. DEX:dexamethasone; EtOH: ethanol.

FIG. 7: Therapeutic administration of MAB #1 dose-dependently reducesthe thickening of epidermal and dermal skin layer induced by topicaladministration of MC903 on ear skin.

Data are presented as individual data points (n=10 per group) and meanvalues (horizontal lines)±SEM. Statistical significance versusMC903+MOR03207 was calculated using ANOVA and Dunnett's multiplecomparison test: *p<0.05; **p<0.01; ***p<0.001. Left panel: data forepidermal thickness; Right panel: data for dermal thickness. DEX:dexamethasone; EtOH: ethanol.

FIG. 8: Therapeutic administration of MAB #1 dose-dependently reducesthe dermal infiltration of eosinophils. T cells and mast cells.

Data are presented as individual data points (n=10 per group) and meanvalues (horizontal lines)±SEM. Statistical significance versusMC903+MOR03207 was calculated using ANOVA and Dunnett's multiplecomparison test: *p<0.05: **p<0.01; ***p<0.001. Top left panel: data foreosinophils; Top right panel: data for mast cells; Bottom left panel:data for T cells. DEX: dexamethasone; EtOH: ethanol.

FIG. 9: Therapeutic administration of MAB #1 reduces expression ofIL-33, IL-4 and S100A9, which were still increased at Day 16 (11 daysafter stopping MC903 application).

Data are presented as individual data points (n=10 per group) and meanvalues (horizontal lines)±SEM. Statistical significance versusMC903+MOR03207 group was calculated using ANOVA and Dunnett's multiplecomparison test: *p<0.05; **p<0.01; ***p<0.001. Top left panel: data forS100A9 mRNA expression in ear; Bottom left panel: data for IL-4 mRNAexpression in ear; Top right panel: data for IL-33 protein levels inear.

FIG. 10: MAB #1 reduces macroscopic clinical signs of AD-likeinflammation in the spontaneous & chronic Flaky Tail model

Clinical scoring of cutaneous inflammation for each mouse was done atstart (week 0) and at end (week 6) of treatment. Data are the mean±SDfor each treatment group (n=8 per group). Statistical significanceversus the isotype antibody treated group was calculated using ANOVA andDunnett's multiple comparison test (*p<0.05; **p<0.01; ***p<0.001).

FIG. 11: MAB #1 reduces eczematous-like eyelid inflammation in thespontaneous & chronic Flaky Tail model.

Skin eyelid inflammation was scored at end of the treatment (week 6).Data are the mean±SD for each treatment group (n=8 per group).Statistical significance versus the isotype antibody treated group wascalculated using ANOVA and Dunnett's multiple comparison test (*p<0.05;**p<0.01; ***p<0.001).

DETAILED DESCRIPTION OF THE INVENTION

The disclosure pertains to a number of antibodies or antibody fragmentsthat recognize human IL-17C.

Definitions

The term ″IL-17C″ refers to a protein known as interleukin 17C,Human L-17C has the amino acid sequence of (UniProt Q9P0M4):(SEQ ID No.: 1) MTLLPGLLFLTWLHTCLAHHDPSLRGHPHSHGTPHCYSAEELPLGQAPPHLLARGAKWGQALPVALVSSLEAASHRGRHERPSATTQCPVLRPEEVLEADTHQRSISPWRYRVDTDEDRYPQKLAFAECLCRGCIDARTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIHVPVGCTCVLPRSVMouse IL-17C has the amino acid sequence of (UniProt Q8K4C5):(SEQ ID No.: 2) MSLLLLGWLPTGMTHQDPPSWGKPRSHRTLRCYSAEELSHGQAPPHLLTRSARWEQALPVALVASLEATGHRRQHEGPLAGTQCPVLRPEEVLEADTHERSISPWRYRIDTDENRYPQKLAVAECLCRGCINAKTGRETAALNSVQLLQSLLVLRRQPCSRDGTADPTPGSFAFHTEFIRVPVGCTCVLPRSTQCynomolgus monkey IL-17C has the amino acid sequence of (XP_005592825.1):(SEQ ID No.: 3) MTLLPGLLFLTWLHACLAHQDPFLRGHPHTHGTPRCYSAEELPLGQAPPHLLARGAKWGQALPVALVSSLEAAGHRRRHDRPSAATQCPVLRPEEVLEADTHQRSISPWRYRVDTDEDRYPQKLAFAECLCRGCIDPRTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIRVPVGCTCVLPRSV The term ″IL17RA″refers to a protein known as interleukin 17 receptor A. HumanIL17RA has the amino acid sequence of (UniProt Q96F46): (SEQ ID No.: 4)MGAARSPPSAVPGPLLGLLLLLLGVLAPGGASLRLLDHRALVCSQPGLNCTVKNSTCLDDSWIHPRNLTPSSPKDLQIQLHFAHTQQGDLFPVAHIEWTLQTDASILYLEGAELSVLQLNTNERLCVRFEELSKLRHHHRRWRFTESHFVVDPDQEYEVTVHHLPKPIPDGDPNHQSKNFLVPDCEHARMKVTTPCMSSGSLWDPNITVETLEAHQLRVSFTLWNESTHYQILLTSFPHMENHSCFEHMHHIPAPRPEEFHQRSNVTLTLRNLKGCCRHQVQIQPFFSSCLNDCLRHSATVSCPEMPDTPEPIPDYMPLWVYFITGISILLVGSVILLIVCMTWRLAGPGSEKYSDDTKYTDGLPAADLIPPPLKPRKVWIIYSADHPLYVDVVLKFAQFLLTACGTEVALDLLEEQAISEAGVMTWVGRQKQEMVESNSKIIVLCSRGTRAKWQALLGRGAPVRLRCDHGKPVGDLFTAAMNMILPDFKRPACFGTYVVCYFSEVSCDGDVPDLFGAAPRYPLMDRFEEVYFRIQDLEMFQPGRMHRVGELSGDNYLRSPGGRQLRAALDRFRDWQVRCPDWFECENLYSADDQDAPSLDEEVFEEPLLPPGTGIVKRAPLVREPGSQACLAIDPLVGEEGGAAVAKLEPHLQPRGQPAPQPLHTLVLAAEEGALVAAVEPGPLADGAAVRLALAGEGEACPLLGSPGAGRNSVLFLPVDPEDSPLGSSTPMASPDLLPEDVREHLEGLMLSLFEQSLSCQAQGGCSRPAMVLTDPHTPYEEEQRQSVQSDQGYISRSSPQPPEGLTEMEEEEEEEQDPGKPALPLSPEDLESLRSLQRQLLFRQLQKNSGWDTMGSESEGPSA The term ″IL17RE″refers to a protein known as interleukin 17 receptor E. HumanIL17RE has the amino acid sequence of (UniProt Q8NFR9): (SEQ ID No.: 5)MGSSRLAALLLPLLLIVIDLSDSAGIGFRHLPHWNTRCPLASHTDDSFTGSSAYIPCRTWWALFSTKPWCVRVWHCSRCLCQHLLSGGSGLQRGLFHLLVQKSKKSSTFKFYRRHKMPAPAQRKLLPRRHLSEKSHHISIPSPDISHKGLRSKRTQPSDPETWESLPRLDSQRHGGPEFSFDLLPEARAIRVTISSGPEVSVRLCHQWALECEELSSPYDVQKIVSGGHTVELPYEFLLPCLCIEASYLQEDTVRRKKCPFQSWPEAYGSDFWKSVHFTDYSQHTQMVMALTLRCPLKLEAALCQRHDWHTLCKDLPNATARESDGWYVLEKVDLHPQLCFKFSFGNSSHVECPHQTGSLTSWNVSMDTQAQQLILHFSSRMHATFSAAWSLPGLGQDTLVPPVYTVSQARGSSPVSLDLIIPFLRPGCCVLVWRSDVQFAWKHLLCPDVSYRHLGLLILALLALLTLLGVVLALTCRRPQSGPGPARPVLLLHAADSEAQRRLVGALAELLRAALGGGRDVIVDLWEGRHVARVGPLPWLWAARTRVAREQGTVLLLWSGADLRPVSGPDPRAAPLLALLHAAPRPLLLLAYFSRLCAKGDIPPPLRALPRYRLLRDLPRLLRALDARPFAEATSWGRLGARQRRQSRLELCSRLEREAARLADLGMurine IL17RE has the amino acid sequence of (UniProt Q8BH06):(SEQ ID No.: 6) MGSPRLAALLLSLPLLLIGLAVSARVACPCLRSWTSHCLLAYRVDKRFAGLQWGWFPLLVRKSKSPPKFEDYWRHRTPASFQRKLLGSPSLSEESHRISIPSSAISHRGQRTKRAQPSAAEGREHLPEAGSQKCGGPEFSFDLLPEVQAVRVTIPAGPKASVRLCYQWALECEDLSSPFDTQKIVSGGHTVDLPYEFLLPCMCIEASYLQEDTVRRKKCPFQSWPEAYGSDFWQSIRFTDYSQHNQMVMALTLRCPLKLEASLCWRQDPLTPCETLPNATAQESEGWYILENVDLHPQLCFKFSFENSSHVECPHQSGSLPSWTVSMDTQAQQLTLHFSSRTYATFSAAWSDPGLGPDTPMPPVYSISQTQGSVPVTLDLIIPFLRQENCILVWRSDVHFAWKHVLCPDVSHRHLGLLILALLALTALVGVVLVLLGRRLLPGSGRTRPVLLLHAADSEAQRRLVGALAELLRTALGGGRDVIVDLWEGTHVARIGPLPWLWAARERVAREQGTVLLLWNCAGPSTACSGDPQAASLRTLLCAAPRPLLLAYFSRLCAKGDIPRPLRALPRYRLLRDLPRLLRALDAQPATLASSWSHLGAKRCLKNRLEQCHLLELEAAKDDYQGSTNSPCGFSCL

The terms “antagonist of IL-17C” and an “IL-17C antagonist”, are usedinterchangeably herein and refer to any molecule which inhibits theactivity or function of IL-17C. The term “IL-17C antagonist” includes,but is not limited to, antibodies or antibody fragments specificallybinding to IL-17C. Preferably, an IL-17C antagonist in the presentdisclosure is an antibody specific for human IL-17C. Such an antibodymay be of any type, such as a murine, a rat, a chimeric, a humanized ora human antibody,

The term “antibody” as used herein refers to a protein comprising atleast two heavy (H) chains and two light (L) chains inter-connected bydisulfide bonds which interacts with an antigen. Each heavy chain iscomprised of a heavy chain variable region (abbreviated herein as VH)and a heavy chain constant region. The heavy chain constant region iscomprised of three domains, CH1, CH2 and CH3. Each light chain iscomprised of a light chain variable region (abbreviated herein as VL)and a light chain constant region. The light chain constant region iscomprised of one domain, CL. The VH and VL regions can be furthersubdivided into regions of hypervariability, termed complementaritydetermining regions (CDR), interspersed with regions that are moreconserved, termed framework regions (FR). Each VH and VL is composed ofthree CDRs and four FR's arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, and FR4. The variable regions of the heavy and light chainscontain a binding domain that interacts with an antigen. The constantregions of the antibodies may mediate the binding of the immunoglobulinto host tissues or factors, including various cells of the immune system(e.g., effector cells) and the first component (Clq) of the classicalcomplement system. The term “antibody” includes for example, monoclonalantibodies, human antibodies, humanized antibodies, camelised antibodiesand chimeric antibodies. The antibodies can be of any isotype (e.g.,IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4,IgA1 and IgA2) or subclass. Both the light and heavy chains are dividedinto regions of structural and functional homology.

The phrase “antibody fragment”, as used herein, refers to one or moreportions of an antibody that retain the ability to specifically interactwith (e.g., by binding, steric hindrance, stabilizing spatialdistribution) an antigen. Examples of binding fragments include, but arenot limited to, a Fab fragment, a monovalent fragment consisting of theVL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragmentcomprising two Fab fragments linked by a disulfide bridge at the hingeregion; a Fd fragment consisting of the VH and CH1 domains; a Fvfragment consisting of the VL and VH domains of a single arm of anantibody; a dAb fragment (Ward et al., (1989) Nature 341:544-546), whichconsists of a VH domain; and an isolated complementarity determiningregion (CDR). Furthermore, although the two domains of the Fv fragment,VL and VH, are coded for by separate genes, they can be joined, usingrecombinant methods, by a synthetic linker that enables them to be madeas a single protein chain in which the VL and VH regions pair to formmonovalent molecules (known as single chain Fv (scFv); see e.g., Bird etat, (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl.Acad. Sci. 85:5879-5883). Such single chain antibodies are also intendedto be encompassed within the term “antibody fragment”. These antibodyfragments are obtained using conventional techniques known to those ofskill in the art, and the fragments are screened for utility in the samemanner as are intact antibodies. Antibody fragments can also beincorporated into single domain antibodies, maxibodies, minibodies,intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv(see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology23:1126-1136). Antibody fragments can be grafted into scaffolds based onpolypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No.6,703,199, which describes fibronectin polypeptide monobodies). Antibodyfragments can be incorporated into single chain molecules comprising apair of tandem Fv segments (VH-CH1-VH-CH1) which, together withcomplementary light chain polypeptides, form a pair of antigen-bindingsites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Pat. No.5,641,870).

A “human antibody” or “human antibody fragment”, as used herein,includes antibodies and antibody fragments having variable regions inwhich both the framework and CDR regions are derived from sequences ofhuman origin. Furthermore, if the antibody contains a constant region,the constant region also is derived from such sequences. Human originincludes, e.g., human germline sequences, or mutated versions of humangermline sequences or antibody containing consensus framework sequencesderived from human framework sequences analysis, for example, asdescribed in Knappik et al., (2000) J Mol Biol 296:57-86).

The structures and locations of immunoglobulin variable domains, e.g.,CDRs, may be defined using well known numbering schemes, e.g., the Kabatnumbering scheme, the Chothia numbering scheme, or a combination ofKabat and Chothia (see, e.g., Sequences of Proteins of ImmunologicalInterest, U.S. Department of Health and Human Services (1991), eds.Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabatet al., (1991) Sequences of Proteins of Immunological Interest. 5thedit., NIH Publication no. 91-3242 U.S. Department of Health and HumanServices; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia etal., (1989) Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol.Biol. 273:927-948.

A “humanized antibody” or “humanized antibody fragment” is definedherein as an antibody molecule which has constant antibody regionsderived from sequences of human origin and the variable antibody regionsor parts thereof or only the CDRs are derived from another species. Forexample a humanized antibody can be CDR-grafted, wherein the CDRs of thevariable domain are from a non-human origin, while one or moreframeworks of the variable domain are of human origin and the constantdomain (if any) is of human origin.

The term “chimeric antibody” or “chimeric antibody fragment” is definedherein as an antibody molecule which has constant antibody regionsderived from, or corresponding to, sequences found in one species andvariable antibody regions derived from another species. Preferably, theconstant antibody regions are derived from, or corresponding to,sequences found in humans, and the variable antibody regions (e.g. VH,VL, CDR or FR regions) are derived from sequences found in a non-humananimal, e.g. a mouse, rat, rabbit or hamster.

The term “isolated” refers to a compound, which can be e.g. an antibodyor antibody fragment, that is substantially free of other antibodies orantibody fragments having different antigenic specificities. Moreover,an isolated antibody or antibody fragment may be substantially free ofother cellular material and/or chemicals. Thus, in some aspects,antibodies provided are isolated antibodies which have been separatedfrom antibodies with a different specificity. An isolated antibody maybe a monoclonal antibody. An isolated antibody may be a recombinantmonoclonal antibody. An isolated antibody that specifically binds to anepitope, isoform or variant of a target may, however, havecross-reactivity to other related antigens, e.g., from other species(e.g., species homologs).

The term “recombinant antibody”, as used herein, includes all antibodiesthat are prepared, expressed, created or segregated by means notexisting in nature. For example antibodies isolated from a host celltransformed to express the antibody, antibodies selected and isolatedfrom a recombinant, combinatorial human antibody library, and antibodiesprepared, expressed, created or isolated by any other means that involvesplicing of all or a portion of a human immunoglobulin gene, sequencesto other DNA sequences or antibodies isolated from an animal (e.g., amouse) that is transgenic or transchromosomal for human immunoglobulingenes or a hybridoma prepared therefrom. Preferably, such recombinantantibodies have variable regions in which the framework and CDR regionsare derived from human germline immunoglobulin sequences. In certainembodiments, however, such recombinant human antibodies can be subjectedto in vitro mutagenesis (or, when an animal transgenic for human Igsequences is used, in vivo somatic mutagenesis) and thus the amino acidsequences of the VH and VL regions of the recombinant antibodies aresequences that, while derived from and related to human germline VH andVL sequences, may not naturally exist within the human antibody germlinerepertoire in vivo. A recombinant antibody may be a monoclonal antibody.In an embodiment, the antibodies and antibody fragment disclosed hereinare isolated from the Ylanthia® antibody library as disclosed in U.S.Ser. No. 13/321,564 or U.S. Ser. No. 13/299,367, which both herein areincorporated by reference.

The term “monoclonal antibody” as used herein refers to a preparation ofantibody molecules of single molecular composition. A monoclonalantibody composition displays a unique binding site having a uniquebinding specificity and affinity for particular epitopes.

As used herein the term “binds specifically to”, “specifically bindsto”, is “specific to/for” or “specifically recognizes”, or the like,refers to measurable and reproducible interactions such as bindingbetween a target and an antibody or antibody fragment, which isdeterminative of the presence of the target in the presence of aheterogeneous population of molecules including biological molecules.For example, an antibody or antibody fragment that specifically binds toa target (which can be an antigen or an epitope of an antigen) is anantibody or antibody fragment that binds this target with greateraffinity, avidity, more readily, and/or with greater duration than itbinds to other targets. In certain embodiments, an antibody or antibodyfragment specifically binds to an epitope on a protein that is conservedamong the protein from different species. In another embodiment,specific binding can include, but does not require exclusive binding.The antibodies or antibody fragments disclosed herein specifically bindto human IL-17C. Preferably, the disclosed antibodies or antibodyfragments specific for human IL-17C specifically bind to IL-17C ofanother species, such as IL-17C from mouse, rat, rhesus monkey and/orcynomolgus monkey. Even more preferred the antibodies or antibodyfragments disclosed herein are specific for human IL-17C, cynomolgusmonkey IL-17C and mouse IL-17C. Methods for determining whether twomolecules specifically bind are well known in the art and include, forexample, a standard ELISA assay. The scoring may be carried out bystandard color development (e.g. secondary antibody with horseradishperoxide and tetramethyl benzidine with hydrogen peroxide). The reactionin certain wells is scored by the optical density, for example, at 450nm. Typical background (=negative reaction) may be 0.1 OD; typicalpositive reaction may be 1 OD. This means the differencepositive/negative can be more than 5-fold. Typically, determination ofbinding specificity is performed by using not a single referenceantigen, but a set of about three to five unrelated antigens, such asmilk powder, BSA, transferrin or the like.

The term “avidity” is used to describe the combined strength of multiplebond interactions between proteins. Avidity is distinct from affinitywhich describes the strength of a single bond. As such, avidity is thecombined synergistic strength of bond affinities (functional affinity)rather than the sum of bonds. With the antibodies of the presentdisclosure, both antigen-binding sites from the VH/VL pairssimultaneously interact with IL-17C. Whilst each single bindinginteraction may be readily broken (depending on the relative affinity),because many binding interactions are present at the same time,transient unbinding of a single site does not allow the molecule todiffuse away, and binding of that site is likely to be reinstated. Theoverall effect is synergistic, strong binding of antigen to antibody.

As used herein, the term “affinity” refers to the strength ofinteraction between the polypeptide and its target at a single site.Within each site, the binding region of the polypeptide interactsthrough weak non-covalent forces with its target at numerous sites; themore interactions, the stronger the affinity.

The term “K_(D)”, as used herein, refers to the dissociation constant,which is obtained from the ratio of K_(d), to K_(a) (i.e. K_(d)/K_(a))and is expressed as a molar concentration (M). K_(D) values for antigenbinding moieties like e.g. monoclonal antibodies can be determined usingmethods well established in the art. Methods for determining the K_(D)of an antigen binding moiety like e.g. a monoclonal antibody are SET(soluble equilibrium titration) or surface plasmon resonance using abiosensor system such as a Biacore® system. In the present disclosure anantibody specific to IL-17C typically has a dissociation rate constant(K_(D)) (k_(off)/k_(on)) of less than 5×10⁻²M, less than 10⁻²M, lessthan 5×10⁻³M, less than 10⁻³M, less than 5×10⁻⁴M, less than 10⁻⁴M, lessthan 5×10⁻⁵M, less than 10⁻⁵M, less than 5×10⁻⁸M, less than 10⁻⁸M, lessthan 5×10⁻⁷M, less than 10⁻⁷M, less than 5×10⁻⁸M, less than 10⁻⁸M, lessthan 5×10⁻⁹M, less than 10⁻⁹M, less than 5×10⁻¹° M, less than 10⁻¹⁰M,less than 5×10⁻¹¹M, less than 10⁻¹¹M, less than 5×10⁻¹²M, less than10⁻¹²M, less than 5×10⁻¹³M, less than 10⁻¹³M, less than 5×10⁻¹⁴M, lessthan 10⁻¹⁴M, less than 5×10⁻¹⁵M, or less than 10⁻¹⁵M or lower.

“Cross competes” means the ability of an antibody, antibody fragment orother antigen-binding moieties to interfere with the binding of otherantibodies, antibody fragments or antigen-binding moieties to a specificantigen in a standard competitive binding assay. The ability or extentto which an antibody, antibody fragment or other antigen-bindingmoieties is able to interfere with the binding of another antibody,antibody fragment or antigen-binding moieties to a specific antigen,and, therefore whether it can be said to cross-compete according to theinvention, can be determined using standard competition binding assays.One suitable assay involves the use of the Biacore technology (e.g. byusing the BIAcore 3000 instrument (Biacore, Uppsala, Sweden)), which canmeasure the extent of interactions using surface plasmon resonancetechnology. Another assay for measuring cross-competing uses anELISA-based approach. A high throughput process for “epitope binning”antibodies based upon their cross-competition is described inInternational Patent Application No. WO 2003/48731. Cross-competition ispresent if the antibody or antibody fragment under investigation reducesthe binding of one of the antibodies described in Table 1 to IL-17C by60% or more, specifically by 70% or more and more specifically by 80% ormore and if one of the antibodies described in Table 1 reduces thebinding of said antibody or antibody fragment to IL-17C by 60% or more,specifically by 70% or more and more specifically by 80% or more.

The term “epitope” includes any proteinacious region which isspecifically recognized by an antibody or fragment thereof or a T-cellreceptor or otherwise interacts with a molecule. Generally epitopes areof chemically active surface groupings of molecules such as amino acidsor carbohydrate or sugar side chains and generally may have specificthree-dimensional structural characteristics, as well as specific chargecharacteristics. As will be appreciated by one of skill in the art,practically anything to which an antibody can specifically bind could bean epitope.

“Binds the same epitope as” means the ability of an antibody, antibodyfragment or other antigen-binding moiety to bind to a specific antigenand binding to the same epitope as the exemplified antibody when usingthe same epitope mapping technique for comparing the antibodies. Theepitopes of the exemplified antibody and other antibodies can bedetermined using epitope mapping techniques. Epitope mapping techniquesare well known in the art. For example, conformational epitopes arereadily identified by determining spatial conformation of amino acidssuch as by, e.g., hydrogen/deuterium exchange, x-ray crystallography andtwo-dimensional nuclear magnetic resonance.

Compositions of the present disclosure may be used for therapeutic orprophylactic applications. The present disclosure, therefore, includes apharmaceutical composition containing an antibody (or functionalantibody fragment) as disclosed herein and a pharmaceutically acceptablecarrier or excipient therefor. In a related aspect, the presentdisclosure provides a method for treating an inflammatory disorder. Suchmethod contains the steps of administering to a subject in need thereofan effective amount of the pharmaceutical composition that contains anantibody (or functional antibody fragment) as described or contemplatedherein.

The present disclosure provides therapeutic methods comprising theadministration of a therapeutically effective amount of an IL-17Cantibody as disclosed to a subject in need of such treatment. A“therapeutically effective amount” or “effective amount”, as usedherein, refers to the amount of an IL-17C antibody necessary to elicitthe desired biological response. In accordance with the subjectinvention, the therapeutic effective amount is the amount of an IL-17Cantibody necessary to treat and/or prevent a disease.

“Subject” or “species”, as used in this context refers to any mammal,including rodents, such as mouse or rat, and primates, such ascynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta)or humans (Homo sapiens). Preferably the subject is a primate, mostpreferably a human.

Embodiments

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C wherein said antibody or antibodyfragment comprises

-   -   (a) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 7, a HCDR2 region comprising the amino acid sequence of SEQ        ID No.: 8, a HCDR3 region comprising the amino acid sequence of        SEQ ID No.: 9, a LCDR1 region comprising the amino acid sequence        of SEQ ID No.: 13, a LCDR2 region comprising the amino acid        sequence of SEQ ID No.: 14 and a LCDR3 region comprising the        amino acid sequence of SEQ ID No.: 15, or    -   (b) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 20, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 21, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 22, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 26, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 27 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 28.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In another embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C wherein said antibody or antibodyfragment comprises

-   -   (a) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 10, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 11, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 12, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 13, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 14 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 15, or    -   (b) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 23, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 24, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 25, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 26, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 27 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 28.

In a further embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C wherein said antibody or antibodyfragment comprises

-   -   (a) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 7, a HCDR2 region comprising the amino acid sequence of SEQ        ID No.: 8, a HCDR3 region comprising the amino acid sequence of        SEQ ID No.: 9, a LCDR1 region comprising the amino acid sequence        of SEQ ID No.: 13, a LCDR2 region comprising the amino acid        sequence of SEQ ID No.: 14 and a LCDR3 region comprising the        amino acid sequence of SEQ ID No.: 15, or    -   (b) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 10, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 11, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 12, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 13, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 14 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 15, or    -   (c) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 20, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 21, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 22, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 26, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 27 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 28.    -   (d) a HCDR1 region comprising the amino acid sequence of SEQ ID        No.: 23, a HCDR2 region comprising the amino acid sequence of        SEQ ID No.: 24, a HCDR3 region comprising the amino acid        sequence of SEQ ID No.: 25, a LCDR1 region comprising the amino        acid sequence of SEQ ID No.: 26, a LCDR2 region comprising the        amino acid sequence of SEQ ID No.: 27 and a LCDR3 region        comprising the amino acid sequence of SEQ ID No.: 28.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In another embodiment of the present disclosure the antibody or antibodyfragment specifically binds to human IL-17C.

In another embodiment of the present disclosure the antibody or antibodyfragment is a monoclonal antibody or antibody fragment.

In another embodiment of the present disclosure the antibody or antibodyfragment is a human, humanized or chimeric antibody or antibodyfragment. In another embodiment of the present disclosure the antibodyor antibody fragment is of the IgG isotype. In another embodiment theantibody or antibody fragment is IgG1.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, and further comprises a heavy chain of SEQ ID No.: 17 or a lightchain of SEQ ID No.: 16, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15 and further comprises a heavy chain of SEQ ID No.: 17 or a lightchain of SEQ ID No.: 16, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28 and further comprises a heavy chain of SEQ ID No.: 30 or a lightchain of SEQ ID No.: 29, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, and further comprises a heavy chain of SEQ ID No.: 30 or a lightchain of SEQ ID No.: 29.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises a heavy chain of SEQ ID No.: 17 and a light chain ofSEQ ID No.: 16.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises a heavy chain of SEQ ID No.: 30 and a light chain ofSEQ ID No.: 29.

In a further embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises a heavy chain of SEQ ID No.: 43 and a light chain ofSEQ ID No.: 42.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C, wherein said antibody or antibodyfragment comprises a heavy chain of SEQ ID No.: 56 and a light chain ofSEQ ID No.: 55.

In another embodiment of the present disclosure the antibody or antibodyfragment is an isolated antibody or antibody fragment.

In another embodiment of the present disclosure the antibody or antibodyfragment is a recombinant antibody or antibody fragment.

In one embodiment, the present disclosure refers to an antibody orantibody fragment specific for IL-17C for use in the treatment of adisorder or condition associated with the undesired presence of IL-17C.

In one embodiment, the present disclosure refers to a nucleic acidcomposition comprising a nucleic acid sequence or a plurality of nucleicacid sequences encoding an antibody or antibody fragment specific forIL-17C, wherein said antibody or antibody fragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In another embodiment, the present disclosure refers to a vectorcomposition comprising a vector or a plurality of vectors comprising thenucleic acid sequence or plurality of nucleic acid sequences encoding anantibody or antibody fragment as disclosed in Table 1.

In one embodiment, the present disclosure refers to a cell comprising avector composition comprising a vector or a plurality of vectorscomprising the nucleic acid sequence or plurality of nucleic acidsequences encoding an antibody or antibody fragment as disclosed inTable 1.

In another embodiment, the present disclosure refers to a pharmaceuticalcomposition comprising an antibody or antibody fragment as disclosed inTable 1 and a pharmaceutically acceptable carrier or excipient.

In one embodiment, said antibody or antibody fragment specific forIL-17C blocks the binding of IL-17C to the receptor of IL-17C. In afurther embodiment, said antibody or antibody fragment specific forIL-17C blocks the binding of IL-17C to the receptor of IL-17C, whereinsaid receptor is IL17RE. In another embodiment the present disclosurerefers to an antibody or antibody fragment specific for IL-17C, whereinsaid antibody or antibody fragment blocks the binding of IL-17C toIL17RE. In another embodiment said antibody or antibody fragmentcomprises the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ IDNo.: 8, the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ IDNo.: 13, the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQID No.: 15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In another embodiment said antibody or antibody fragment comprises aheavy chain of SEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or aheavy chain of SEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or aheavy chain and a light chain that has at least 60%, at least 70%, atleast 80%, at least 90% or at least 95% identity to the a heavy chain ofSEQ ID No.: 17 or 30 and to the light chain of SEQ ID No.: 16 or 29.

In another embodiment the present disclosure refers to an antibody orantibody fragment specific for IL-17C wherein said antibody or antibodyfragment bivalently binds to an IL-17C homodimer and forms a complexconsisting of said antibody or antibody fragment and one IL-17Chomodimer and wherein said antibody or antibody fragment blocks thebinding of IL-17C to IL17RE.

In certain embodiments, said antibody or antibody fragment specific forIL-17C blocks the binding of IL-17C to one or more receptors of IL-17C.In another embodiment said antibody or antibody fragment comprises theHCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8, theHCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13, theLCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.: 15,or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28.

In another embodiment said antibody or antibody fragment comprises aheavy chain of SEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or aheavy chain of SEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or aheavy chain and a light chain that has at least 60%, at least 70%, atleast 80%, at least 90% or at least 95% identity to the a heavy chain ofSEQ ID No.: 17 or 30 and to the light chain of SEQ ID No.: 16 or 29.

In alternative embodiments, said antibody or antibody fragment specificfor the receptor of IL-17C blocks the binding of IL-17C to receptors ofIL-17C, wherein the receptors of IL-17C include IL17RE and IL17RA. Inalternative embodiments, said antibody or antibody fragment specific forthe receptor of IL-17C blocks the binding of IL-17C to IL17RE andIL17RA. In certain embodiments, said antibody or antibody fragmentspecific for IL-17C blocks the binding of IL-17C to IL17RE with an IC₅₀concentration of less than 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM,1 nM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM or 1 pM. In certainaspects the IC₅₀ concentration can be determined by ELISA; SET, FACS orMSD (Meso Scale Discovery). In another aspect the IC₅₀ concentration canbe determined by the method as described herein in Example 3. In anotherembodiment said antibody or antibody fragment comprises a heavy chain ofSEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or a heavy chain ofSEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or a heavy chain anda light chain that has at least 60%, at least 70%, at least 80%, atleast 90% or at least 95% identity to the a heavy chain of SEQ ID No.:17 or 30 and to the light chain of SEQ ID No.: 16 or 29.

In one embodiment the disclosed antibody or antibody fragment isspecific for human IL-17C. In a further embodiment the disclosedantibody or antibody fragment specific for IL-17C is cross-reactive withIL-17C of another species, such as IL-17C from mouse, rat, rhesus monkeyand/or cynomolgus monkey. In another embodiment the antibody or antibodyfragment is specific for human IL-17C, cynomolgus monkey IL-17C andmouse IL-17C. In a further embodiment the antibody or antibody fragmentis specific for human IL-17C, cynomolgus monkey IL-17C and mouse IL-17C.In another embodiment the antibody or antibody fragment is specific forhuman IL-17C, cynomolgus monkey IL-17C and mouse IL-17C, wherein saidantibody or antibody fragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28. In another embodiment said antibody or antibody fragment comprises aheavy chain of SEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or aheavy chain of SEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or aheavy chain and a light chain that has at least 60%, at least 70%, atleast 80%, at least 90% or at least 95% identity to the a heavy chain ofSEQ ID No.: 17 or 30 and to the light chain of SEQ ID No.: 16 or 29.

In yet another embodiment the disclosed antibody or antibody fragmentspecifically binds to human IL-17C, cynomolgus monkey IL-17C and mouseIL-17C and blocks the binding of human IL-17C, cynomolgus monkey IL-17Cand mouse IL-17C to its specific receptor IL17RE with an 1050concentration of less than 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM,1 nM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM or 1 pM. In anotheraspect said antibody is in IgG1 format. In another embodiment said IC₅₀concentration is determined in a Receptor Inhibition Assay as describedherein in Example 3.

In yet another embodiment the disclosed antibody or antibody fragmentspecifically binds to human IL-17C and blocks the binding of humanIL-17C to human IL17RE with an IC₅₀ concentration of less than 100 nM,90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 100 pM, 90 pM, 80 pM, 70pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5pM, 4 pM, 3 pM, 2 pM or 1 pM. In another aspect said antibody is in IgG1format. In another embodiments said IC₅₀ concentration is determined ina Receptor Inhibition Assay as described herein in Example 3.

In yet another embodiment the disclosed antibody or antibody fragmentspecifically binds to cynomolgus monkey IL-17C and blocks the binding ofcynomolgus monkey IL-17C to cynomolgus monkey IL17RE with an IC₅₀concentration of less than 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM,1 nM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM or 1 pM. In anotheraspect said antibody is in IgG1 format. In another embodiments said IC₅₀concentration is determined in a Receptor Inhibition Assay as describedherein in Example 3.

In yet another embodiment the disclosed antibody or antibody fragmentspecifically binds to human IL-17C, cynomolgus monkey IL-17C and mouseIL-17C, and blocks the binding of human IL-17C, cynomolgus monkey IL-17Cand mouse IL-17C, to human IL17RE, cynomolgus monkey IL17RE and mouseIL17RE, respectively, each with an IC₅₀ concentration of less than 100nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM,8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 100 pM, 90 pM, 80 pM, 70pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5pM, 4 pM, 3 pM, 2 pM or 1 pM. In a preferred embodiment said antibody orantibody fragment comprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28. In another embodiment said antibody or antibody fragment comprises aheavy chain of SEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or aheavy chain of SEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or aheavy chain and a light chain that has at least 60%, at least 70%, atleast 80%, at least 90% or at least 95% identity to the heavy chain ofSEQ ID No.: 17 or 30 and to the light chain of SEQ ID No.: 16 or 29. Inanother aspect said antibody is in IgG1 format. In another embodimentssaid IC₅₀ concentration is determined in a Receptor Inhibition Assay asdescribed herein in Example 3.

In yet another embodiment the disclosed antibody or antibody fragmentinhibits human IL-17C, cynomolgus monkey IL-17C and mouse IL-17C drivenactivation of a NF-κB reporter gene in NIH3T3 cells with an IC₅₀concentration of less than 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pMor 1 pM. In a preferred embodiment said antibody or antibody fragmentcomprises

the HCDR1 region of SEQ ID No.: 7, the HCDR2 region of SEQ ID No.: 8,the HCDR3 region of SEQ ID No.: 9, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 10, the HCDR2 region of SEQ ID No.: 11,the HCDR3 region of SEQ ID No.: 12, the LCDR1 region of SEQ ID No.: 13,the LCDR2 region of SEQ ID No.: 14 and the LCDR3 region of SEQ ID No.:15, or

the HCDR1 region of SEQ ID No.: 20, the HCDR2 region of SEQ ID No.: 21,the HCDR3 region of SEQ ID No.: 22, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28, or

the HCDR1 region of SEQ ID No.: 23, the HCDR2 region of SEQ ID No.: 24,the HCDR3 region of SEQ ID No.: 25, the LCDR1 region of SEQ ID No.: 26,the LCDR2 region of SEQ ID No.: 27 and the LCDR3 region of SEQ ID No.:28. In another embodiment said antibody or antibody fragment comprises aheavy chain of SEQ ID No.: 17 and a light chain of SEQ ID No.: 16 or aheavy chain of SEQ ID No.: 30 and a light chain of SEQ ID No.: 29 or aheavy chain and a light chain that has at least 60%, at least 70%, atleast 80%, at least 90% or at least 95% identity to the heavy chain ofSEQ ID No.: 17 or 30 and to the light chain of SEQ ID No.: 16 or 29. Inanother aspect said antibody is in IgG1 format. In another embodimentssaid IC₅₀ concentration is determined in a IL-17C-driven NF-κB reporterassay as described herein in Example 4.

In one embodiment the disclosed antibody or antibody fragment isspecific for human IL-17C encoded by the amino acid sequence of SEQ IDNo.: 1. In one embodiment the disclosed antibody or antibody fragment isspecific for a polypeptide comprising the amino acid sequence of SEQ IDNo.: 1. In a further embodiment said monoclonal antibody or antibodyfragment is a monoclonal antibody specific for a polypeptide consistingof the amino acid sequence of SEQ ID No.: 1. In another embodiment thedisclosed antibody or antibody fragment is specific for human IL-17Cencoded by the amino acid sequence of SEQ ID No.: 1 and is a monoclonalantibody or antibody fragment.

In one embodiment the disclosed antibody or antibody fragment specificfor IL-17C is a monoclonal antibody or antibody fragment.

In one embodiment the disclosed antibody or antibody fragment specificfor IL-17C is a human, humanized or chimeric antibody. In certainembodiments, said antibody or antibody fragment specific for IL-17C isan isolated antibody or antibody fragment. In another embodiment saidantibody or antibody fragment is a recombinant antibody or antibodyfragment. In a further embodiment said antibody or antibody fragment isa recombinant human antibody or antibody fragment. In a furtherembodiment said recombinant human antibody or antibody fragment is anisolated recombinant human antibody or antibody fragment. In a furtherembodiment said recombinant human antibody or antibody fragment orisolated recombinant human antibody or antibody fragment is monoclonal.

In another embodiment the disclosed antibody or antibody fragmentcomprises a heavy chain of SEQ ID No.: 17 and a light chain of SEQ IDNo.: 16 or a heavy chain of SEQ ID No.: 30 and a light chain of SEQ IDNo.: 29 or a heavy chain and a light chain that has at least 60%, atleast 70%, at least 80%, at least 90% or at least 95% identity to the aheavy chain of SEQ ID No.: 17 or 30 and to the light chain of SEQ IDNo.: 16 or 29.

In one embodiment the disclosed antibody or antibody fragment comprisesa human heavy chain constant region and a human light chain constantregion. In a further embodiment said human heavy chain constant regioncomprises the amino acid sequences of SEQ ID No.: 17 and the human lightchain constant region comprises the amino acid sequences of SEQ ID No.:16 or said human heavy chain constant region comprises the amino acidsequences of SEQ ID No.: 30 and the human light chain constant regioncomprises the amino acid sequences of SEQ ID No.: 29.

In one embodiment the disclosed antibody or antibody fragment is of theIgG isotype. In another embodiment said antibody is IgG1.

In one embodiment said antibody fragment is a bivalent antibodyfragment.

In another embodiment, the present disclosure refers to an antibody orantibody fragment that cross-competes with an antibody described inTable 1. In one embodiment the present disclosure refers to an antibodyor antibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRsdefined by Kabat of one of the antibodies in Table 1, In anotherembodiment the present disclosure refers to an antibody or antibodyfragment specific for human IL-17C wherein said antibody or antibodyfragment bivalently binds to an IL-17C homodimer and forms a complexconsisting of said antibody or antibody fragment and one IL-17Chomodimer and wherein said antibody or antibody fragment cross-competeswith an antibody or antibody fragment comprising 6 CDRs defined by Kabatof one of the antibodies in Table 1.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 7, the HCDR2is the amino acid sequence of SEQ ID No.: 8, the HCDR3 is the amino acidsequence of SEQ ID No.: 9, the LCDR1 is the amino acid sequence of SEQID No.: 13, the LCDR2 is the amino acid sequence of SEQ ID No.: 14 andthe LCDR3 is the amino acid sequence of SEQ ID No.: 15. In anotherembodiment the present disclosure refers to an antibody or antibodyfragment, wherein said antibody or antibody fragment cross-competes withan antibody or antibody fragment comprising the VH according to SEQ IDNo.: 17 and the VL according to SEQ ID No.: 16.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 20, theHCDR2 is the amino acid sequence of SEQ ID No.: 21, the HCDR3 is theamino acid sequence of SEQ ID No.: 22, the LCDR1 is the amino acidsequence of SEQ ID No.: 26, the LCDR2 is the amino acid sequence of SEQID No.: 27 and the LCDR3 is the amino acid sequence of SEQ ID No.: 28.In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising the VHaccording to SEQ ID No.: 30 and the VL according to SEQ ID No.: 29.

In another embodiment, the present disclosure refers to an antibody orantibody fragment that cross-competes with an antibody described inTable 1. In one embodiment the present disclosure refers to an antibodyor antibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRsdefined by Chothia of one of the antibodies in Table 1. In anotherembodiment the present disclosure refers to an antibody or antibodyfragment specific for human IL-17C wherein said antibody or antibodyfragment bivalently binds to an IL-17C homodimer and forms a complexconsisting of said antibody or antibody fragment and one IL-17Chomodimer and wherein said antibody or antibody fragment cross-competeswith an antibody or antibody fragment comprising 6 CDRs defined byChothia of one of the antibodies in Table 1.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 10, theHCDR2 is the amino acid sequence of SEQ ID No.: 11, the HCDR3 is theamino acid sequence of SEQ ID No.: 12, the LCDR1 is the amino acidsequence of SEQ ID No.: 13, the LCDR2 is the amino acid sequence of SEQID No.: 14 and the LCDR3 is the amino acid sequence of SEQ ID No.: 15.In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising the VHaccording to SEQ ID No.: 17 and the VL according to SEQ ID No.: 18.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 23, theHCDR2 is the amino acid sequence of SEQ ID No.: 24, the HCDR3 is theamino acid sequence of SEQ ID No.: 25, the LCDR1 is the amino acidsequence of SEQ ID No.: 26, the LCDR2 is the amino acid sequence of SEQID No.: 27 and the LCDR3 is the amino acid sequence of SEQ ID No.: 28.In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragmentcross-competes with an antibody or antibody fragment comprising the VHaccording to SEQ ID No.: 30 and the VL according to SEQ ID No.: 29.

In a certain embodiment, the disclosure refers to an antibody orantibody fragment that cross-competes with an antibody described inTable 1 and reduces the specific binding of one of the antibodiesdescribed in Table 1 by at least 70%, 80% or 90% in an ELISA-basedcross-competition assay. In a certain embodiment, the present disclosurerefers to an monoclonal antibody or antibody fragment thatcross-competes with an antibody described in Table 1 and reduces thespecific binding of one of the antibodies described in Table 1 to IL-17Cby at least 70%, 80% or 90% in an ELISA-based cross-competition assay. Arepresentative assay set-up is illustrated in Example 6 in the presentdisclosure.

In another embodiment, the present disclosure refers to an antibody orantibody fragment that binds to (e.g., by binding, stabilizing, spatialdistribution) the same epitope as one of the antibodies in Table 1. In afurther embodiment said antibody or antibody fragment binds to (e.g., bybinding, stabilizing, spatial distribution) the same epitope as anantibody or antibody fragment comprising 6 CDRs defined by Kabat of oneof the antibodies in Table 1. In yet another embodiment said antibody orantibody fragment binds to (e.g., by binding, stabilizing, spatialdistribution) the same epitope of IL-17C as an antibody or antibodyfragment comprising 6 CDRs defined by Kabat of one of the antibodies inTable 1. In yet another embodiment said antibody or antibody fragmentbinds to (e.g., by binding, stabilizing, spatial distribution) the sameepitope of polypeptide comprising the amino acid sequence of SEQ ID No.:1 as an antibody or antibody fragment comprising 6 CDRs defined by Kabatof one of the antibodies in Table 1.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragment binds tothe same epitope as an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 10, theHCDR2 is the amino acid sequence of SEQ ID No.: 11, the HCDR3 is theamino acid sequence of SEQ ID No.: 12, the LCDR1 is the amino acidsequence of SEQ ID No.: 13, the LCDR2 is the amino acid sequence of SEQID No.: 14 and the LCDR3 is the amino acid sequence of SEQ ID No.: 15.In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragment binds tothe same epitope as an antibody or antibody fragment comprising the VHaccording to SEQ ID No.: 17 and the VL according to SEQ ID No.: 18.

In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragment binds tothe same epitope as an antibody or antibody fragment comprising 6 CDRs,wherein the HCDR1 is the amino acid sequence of SEQ ID No.: 23, theHCDR2 is the amino acid sequence of SEQ ID No.: 24, the HCDR3 is theamino acid sequence of SEQ ID No.: 25, the LCDR1 is the amino acidsequence of SEQ ID No.: 26, the LCDR2 is the amino acid sequence of SEQID No.: 27 and the LCDR3 is the amino acid sequence of SEQ ID No.: 28.In another embodiment the present disclosure refers to an antibody orantibody fragment, wherein said antibody or antibody fragment binds tothe same epitope as an antibody or antibody fragment comprising the VHaccording to SEQ ID No.: 30 and the VL according to SEQ ID No.: 29.

Regions of a given polypeptide that include an epitope can be identifiedusing any number of epitope mapping techniques, well known in the art.See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology,Vol. 66 (Glenn E. Morris, Ed., 1996) Humana Press, Totowa, N.J. Forexample, epitopes may be determined by e.g., concurrently synthesizinglarge numbers of peptides on solid supports, the peptides correspondingto portions of the protein molecule, and reacting the peptides withantibodies while the peptides are still attached to the supports. Suchtechniques are known in the art and described in, e.g., U.S. Pat. No.4,708,871; Geysen et al., (1984) Proc. Natl. Acad. Sci. USA 8:3998-4002;Geysen et al., (1985) Proc. Natl. Acad. Sci. USA 82:78-182; Geysen etal., (1986) Mol. Immunol. 23:709-715. Similarly, epitopes are readilyidentified by determining spatial conformation of amino acids such asby, e.g., hydrogen/deuterium exchange, x-ray crystallography andtwo-dimensional nuclear magnetic resonance. See, e.g., Epitope MappingProtocols, supra. Antigenic regions of proteins can also be identifiedusing standard antigenicity and hydropathy plots, such as thosecalculated using, e.g., the Omiga version 1.0 software program availablefrom the Oxford Molecular Group. This computer program employs theHopp/Woods method, Hopp et al., (1981) Proc. Natl. Acad. Sci USA78:3824-3828; for determining antigenicity profiles, and theKyte-Doolittle technique, Kyte et al., (1982) J. Mol. Biol. 157:105-132;for hydropathy plots.

In one embodiment, the present disclosure refers to an antibody orantibody fragment comprising 6 CDRs defined by Kabat of any of theantibodies in Table 1. In another aspect, the disclosure pertains to anisolated monoclonal antibody or fragment thereof comprising 6 CDRsdefined by Kabat of each of the antibodies in Table 1.

In another embodiment, the present disclosure refers to an antibody orantibody fragment comprising 6 CDRs defined by Chotia of any of theantibodies in Table 1. In another aspect, the disclosure pertains to anisolated monoclonal antibody or fragment thereof comprising 6 CDRsdefined by Chotia of each of the antibodies in Table 1.

In certain embodiments, the present disclosure refers to the antibodiesor antibody fragments disclosed in in Table 1, wherein said antibodiesor antibody fragments can bind to IL-17C with an affinity of about lessthan 100 nM, more preferably less than about 60 nM, and still morepreferably less than about 30 nM. Further preferred are antibodies orantibody fragments that bind to IL-17C with an affinity of less thanabout 10 nM, and more preferably less than about 3 nM.

In certain embodiments, the present disclosure refers to the antibodiesor antibody fragments disclosed in Table 1, wherein said antibodies orantibody fragments can bind to IL-17C with a monovalent affinity ofabout less than 100 nM, more preferably less than about 60 nM, and stillmore preferably less than about 30 nM. Further preferred are antibodiesor antibody fragments that bind to IL-17C with a monovalent affinity ofless than about 10 nM, and more preferably less than about 3 nM.

In another embodiment, the present disclosure refers to antibodies orantibody fragments specific for IL-17C, wherein said antibodies orantibody fragments have a monovalent affinity to IL-17C with adissociation rate constant (K_(D)) of less than 5×10⁻²M, less than10⁻²M, less than 5×10⁻³M, less than 10³M, less than 5×10⁻⁴M, less than10⁻⁴M, less than 5×10⁻⁵M, less than 10⁻⁵M, less than 5×10⁻⁵M, less than10⁻⁵M, less than 5×10⁻⁷M, less than 10⁻⁷M, less than 5×10⁻⁵M, less than10⁻⁵M, less than 5×10⁻⁹M, less than 10⁻⁹M, less than 5×10⁻¹⁰M, less than10⁻¹⁹M, less than 5×10⁻¹¹M, less than 10⁻¹¹M, less than 5×10⁻¹²M, lessthan 10⁻¹²M, less than 5×10⁻¹³M, less than 10⁻¹³M, less than 5×10⁻¹⁴M,less than 10⁻¹⁴M, less than 5×10⁻¹⁵M, or less than 10⁻¹⁵M and whereinsaid antibodies or antibody fragments in a bivalent format have anaffinity to IL-17C with a dissociation rate constant (K_(D)) which is atleast 2-fold, 5-fold, 10-fold, 100-fold, 1000-fold, 10000-fold,100000-fold lower than the dissociation rate constant (KD) in amonovalent format. In a further embodiment the bivalent affinity of saidantibodies or antibody fragments is determined in IgG-format, whereinthe monovalent affinity of said antibodies or antibody fragments isdetermined in Fab-format.

The compositions of the present disclosure are preferably pharmaceuticalcompositions comprising an antibody or antibody fragment specific forIL-17C as disclosed herein and a pharmaceutically acceptable carrier,diluent or excipient, for the treatment of an inflammatory disorder orcancer. Such carriers, diluents and excipients are well known in theart, and the skilled artisan will find a formulation and a route ofadministration best suited to treat a subject with the IL-17C antibodiesor antibody fragments of the present disclosure.

In another embodiment the present disclosure refers to pharmaceuticalcompositions comprising an antibody or antibody fragment specific forIL-17C as disclosed herein for the use in the treatment of a disorder orcondition associated with the undesired presence of IL-17C. In anotherembodiment said condition associated with the undesired presence ofIL-17C is an inflammatory disorder or cancer. In another embodiment saidinflammatory disorder is rheumatoid arthritis, psoriasis, pulmonaryinflammation, COPD and/or atopic dermatitis (AD), includingmoderate-to-severe AD. In a preferred embodiment said inflammatorydisorder is atopic dermatitis (AD) and/or moderate-to-severe AD.

In another embodiment the present disclosure refers to the use of saidpharmaceutical compositions comprising an antibody or antibody fragmentspecific for IL-17C as disclosed herein in the preparation of amedicament for the treatment of a disorder or condition associated withthe undesired presence of IL-17C. In another embodiment said conditionassociated with the undesired presence of IL-17C is an inflammatorydisorder or cancer. In another embodiment said inflammatory disorder isrheumatoid arthritis, psoriasis, pulmonary inflammation, COPD and/oratopic dermatitis (AD), including moderate-to-severe AD. In a preferredembodiment said inflammatory disorder is atopic dermatitis (AD) and/ormoderate-to-severe AD.

In another embodiment the present disclosure refers to the use of saidpharmaceutical composition for the treatment of a disorder or conditionassociated with the undesired presence of IL-17C. In another embodimentsaid condition associated with the undesired presence of IL-17C is aninflammatory disorder or cancer. In another embodiment said inflammatorydisorder is rheumatoid arthritis, psoriasis, pulmonary inflammation,COPD and/or atopic dermatitis (AD), including moderate-to-severe AD. Ina preferred embodiment said inflammatory disorder is atopic dermatitis(AD) and/or moderate-to-severe AD.

In another aspect, provided herein is a method of treating atopicdermatitis (AD) and/or moderate-to-severe atopic dermatitis (AD) in asubject, the method comprising administering a pharmaceuticalcomposition comprising a therapeutically effective amount of the IL-17Cantibodies or antibody fragments of the present disclosure. In oneembodiment said subject is resistant, non-responsive or inadequatelyresponsive to treatment by either a topical corticosteroid (TCS) or acalcineurin inhibitor. In another embodiment the subject is a subject inneed thereof. In a preferred embodiment said subject is a human. Inalternative aspects said subject is a rodent, such as a rat or a mouse.

In another embodiment, the present disclosure refers to a method for theprophylaxis of an inflammatory disorder in a subject, said methodcomprising administering an IL-17C antagonist to said subject.“Prophylaxis” as used in this context refers to methods which aim toprevent the onset of a disease or which delay the onset of a disease. Insome embodiments said subject is a human. In alternative aspects saidsubject is a rodent, such as a rat or a mouse.

In some embodiments, the antibodies or antibody fragments specific forIL-17C of the present disclosure are administered subcutaneously. Inother aspects the antibodies or antibody fragments specific for IL-17Cof the present disclosure are administered intra-venously,intra-articularly or intra-spinally.

In one embodiment, the disclosure pertains to an isolated monoclonalantibody or fragment thereof comprising a VH and a VL of any of theantibodies in Table 1.

In another embodiment, the disclosure pertains to an isolated monoclonalantibody or fragment thereof comprising a Heavy chain (IgG1) and a Lightchain of any of the antibodies in Table 1.

In another embodiment, the disclosure refers to an isolated nucleic acidencoding a heavy chain sequence and/or light chain sequence of anantibody that binds to IL-17C the nucleic acid comprising

a HCDR1 region of SEQ ID No.: 58, the HCDR2 region of SEQ ID No.: 59,the HCDR3 region of SEQ ID No.: 60, the LCDR1 region of SEQ ID No.: 64,the LCDR2 region of SEQ ID No.: 65 and the LCDR3 region of SEQ ID No.:66, or

a HCDR1 region of SEQ ID No.: 61, the HCDR2 region of SEQ ID No.: 62,the HCDR3 region of SEQ ID No.: 63, the LCDR1 region of SEQ ID No.: 64,the LCDR2 region of SEQ ID No.: 65 and the LCDR3 region of SEQ ID No.:66, or

a HCDR1 region of SEQ ID No.: 33, the HCDR2 region of SEQ ID No.: 34,the HCDR3 region of SEQ ID No.: 35, the LCDR1 region of SEQ ID No.: 39,the LCDR2 region of SEQ ID No.: 40 and the LCDR3 region of SEQ ID No.:41, or

a HCDR1 region of SEQ ID No.: 36, the HCDR2 region of SEQ ID No.: 37,the HCDR3 region of SEQ ID No.: 38, the LCDR1 region of SEQ ID No.: 39,the LCDR2 region of SEQ ID No.: 40 and the LCDR3 region of SEQ ID No.:41, or

a HCDR1 region of SEQ ID No.: 46, the HCDR2 region of SEQ ID No.: 47,the HCDR3 region of SEQ ID No.: 48, the LCDR1 region of SEQ ID No.: 52,the LCDR2 region of SEQ ID No.: 53 and the LCDR3 region of SEQ ID No.:54, or

a HCDR1 region of SEQ ID No.: 49, the HCDR2 region of SEQ ID No.: 50,the HCDR3 region of SEQ ID No.: 51, the LCDR1 region of SEQ ID No.: 52,the LCDR2 region of SEQ ID No.: 53 and the LCDR3 region of SEQ ID No.:54.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a VH region of SEQ ID No.: 19 and a VL region of SEQ IDNo.: 18, or a VH region and a VL region that has at least 60%, at least70%, at least 80%, at least 90% or at least 95% identity to the VHregion of SEQ ID No.: 19 and/or the VL region of SEQ ID No.: 18.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a VH region of SEQ ID No.: 68 and a VL region of SEQ IDNo.: 67, or a VH region and a VL region that has at least 60%, at least70%, at least 80%, at least 90% or at least 95% identity to the VHregion of SEQ ID No.: 68 and/or the VL region of SEQ ID No.: 67.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a VH region of SEQ ID No.: 32 and a VL region of SEQ IDNo.: 31, or a VH region and a VL region that has at least 60%, at least70%, at least 80%, at least 90% or at least 95% identity to the VHregion of SEQ ID No.: 32 and/or the VL region of SEQ ID No.: 31.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a Heavy chain (IgG1) of SEQ ID No.: 45 and a Light chainof SEQ ID No.: 44.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a Heavy chain (IgG1) of SEQ ID No.: 70 and a Light chainof SEQ ID No.: 69.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a Heavy chain (IgG1) of SEQ ID No.: 71 and a Light chainof SEQ ID No.: 57.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a VH and a VL of any of the antibodies in Table 1.

In another embodiment, the disclosure refers to a nucleic acid encodingan isolated monoclonal antibody or fragment thereof wherein the nucleicacid comprises a Heavy chain (IgG1) and a Light chain of any of theantibodies in Table 1.

In another embodiment, the disclosure refers to a method of producing anisolated monoclonal antibody or fragment thereof of any of theantibodies in Table 1.

TABLE 1 Antibody sequences Antibody SEQ ID # No.: [aa]/DNA MAB#1HCDR1 (Kabat) SEQ ID No.: 7 DYAMH HCDR2 (Kabat) SEQ ID No : 8YIGGVGEGTQYAESVKG HCDR3 (Kabat) SEQ ID No.: 9 GFAIRYYGFDYHCDR1 (Chothia) SEQ ID No.: 10 GFTVSDY HCDR2 (Chothia) SEQ ID No.: 11GGVGEG HCDR3 (Chothia) SEQ ID No.: 12 GFAIRYYGFDY LCDR1 (Kabat &SEQ ID No.: 13 SGDKLGDKYAY Chothia) LCDR2 (Kabat & SEQ ID No.: 14QDSKRPS Chothia) LCDR3 (Kabat & SEQ ID No.: 15 QVFTFPLVTT Chothia) VLSEQ ID No.: 16 SYELTQPPSVSVSPGQTASITCSGDKLGDKYAYWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGN TATLTISGTQAEDEADYYCQVFTFPLVTTVFGGGTKLTVLGQ VH SEQ ID No.: 17 EVQLLESGGGLVQPGGSLRLSCAASGFTVSDYAMHWVRQAPGKGLEWVSYIGGVGEGTQYAESVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFAIRYYGFDYWGQGTLVTVSS VL (DNA) SEQ ID No.: 18agctatgaactgacccagccgccgagcgttagcgttagcccaggccagaccgccagcattacctgtagcggcgacaaactgggccacaaatacgcctactggtatcagcagaaaccgggccagagcccggtgctggttatctatcaggatagcaaacgcccgagcggcattccagaacgctttagcggcagcaacagcggcaacaccgccaccctgaccattagcggcacccaggccgaagacgaagccgattattactgccaggttttcactttcccgctggttactactgtgtttggcggcggtaccaagctgaccgtgctgggccag VH (DNA) SEQ ID No.: 19gaagtgcagctgctggaaagcggtggcggtctggtgcagccaggtggtagcctgcgcctgagctgtgccgcaagcggcttcacagtgccgactacgcaatgcattgggtgcgccaagcaccaggaaaggcctggaatgggtgagttacataggtggcgtgggtgaggggacacaatatgcagagagcgtgaaaggtcgcttaccattagtcgcgataacagcaaaaacaccctgtatctgcaaatgaacagcctgcgggcagaagataccgcagtttattattgcgcgcgtggtttcgcaatccgttattatggatttgattattggggccagggcaccctggttactgtctcgagc HCDR1 (Kabat) SEQ ID No.: 33 gactacgcaatgcatHCDR2 (Kabat) SEQ ID No.: 34tacataggtggcgtgggtgaggggacacaatatgcagagagcgtga aaggt HCDR3 (Kabat)SEQ ID No.: 35 ggtttcgcaatccgttattatggatttgattat HCDR1 (Chothia)SEQ ID No.: 36 ggcttcacagtgtccgactac HCDR2 (Chothia) SEQ ID No.: 37ggtggcgtgggtgagggg HCDR3 (Chothia) SEQ ID No.: 38ggtttcgcaatccgttattatggatttgattat LCDR1 (Kabat & SEQ ID No.: 39agcggcgacaaactgggcgacaaatacgcctac Chothia) LCDR2 (Kabat & SEQ ID No.: 40caggatagcaaacgcccgagc Chothia) LCDR3 (Kabat & SEQ ID No.: 41caggttttcactttcccgctggttactact Chothia) Light chain SEQ ID No.: 42SYELTQPPSVSVSPGQTASITCSGDKLGDKYAYW YQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQVFTFPLVTTVFGGGT KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Heavy chain SEQ ID No.: 43 EVQLLESGGGLVQPGGSLRLSCAASGFTVSDYAM(IgG1) HWVRQAPGKGLEWVSYIGGVGEGTQYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFAI RYYGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK Light chain SEQ ID No: 44agctatgaactgacccagccgccgagcttagcgttagcccaggcca (DNA)gaccgccagcattacctgtagcggcgacaaactgggcgacaaatacgcctactggtatcagcagaaaccgggccagagcccggtgctggttatctatcaggatagcaaacgcccgagcggcattccagaacgctttagcggcagcaacagcggcaacaccgccaccctgaccattagcggcacccaggccgaagacgaagccgattattactgccaggttttcactttcccgctggttactactgtgtttggcggcggtaccaagctgaccgtgctgggccagcccaaagccgcccctagcgtgaccctgttccccccaagcagcgaggaactccaggccaacaaggccaccctcgtgtgcctgatcagcgacttctaccctggcgccgtgaccgtggcctggaaggccgatagcagccctgtgaaggccggcgtggaaaccaccacccccagcaagcagagcaacaacaaatacgccgccagcagctacctgagcctgacccccgagcagtggaagtcccacagatcctacagctgccaggtcacacacgagggcagcaccgtggaaaagaccgtggcccccaccgagtgcagc Heavy chain SEQ ID No.: 45gaagtgcagctgctggaaagcggtggcggtctggtgcagccaggtgg (IgG1, DNA)tagcctgcgcctgagctgtgccgcaagcggcttcacagtgtccgactacgcaatgcattgggtgcgccaagcaccaggcaaaggcctggaatgggtgagttacatagatggcatgggtgaggggacacaatatgcagagaacgtgaaaggtcgctttaccattagtcgcgataacagcaaaaacaccctgtatctgcaaatgaacagcctgcgggcagaagataccgcagtttattattgcgcgcgtggtttcgcaatccgttattatggatttgattattggggccagggcaccctggttactgtctcgagcgcgtcgaccaaaggccccagcgtgttccctctggcccccagcagcaagagcacctctggcggaacagccgccctgggctgcctggtcaaggactacttccccgagcccgtgaccgtgtcctgaaactctggcgccctgaccagcgacgtgcacacctttccagccgtgctccagagcagcggcctgtacagcctgagcagcgtcgtgaccgtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcccagcaacacaaaggtggacaagcgggtggaacccaagagctgcgacaagacccacacctgtcccccctgccagcccctgaactgctgggaggcccctccgtgttcctgttccccccaaagcctaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccagaagtgaagtttaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaaaggccagccccgcgagccccaggtgtacacactgccccctagccgggaagagatgaccaagaaccaggtgtccctgacctgcctcgtgaagggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctcattcttcctatacagcaagctgaccgtggacaagagccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgaacctaagccccggcaag DNA (optimized) HCDR1 (Kabat)SEQ ID No.: 58 gactacgctatgcac HCDR2 (Kabat) SEQ ID No.: 59tatatcggcggcgtgggcgagggcacccagtacgctaagtctgtgaa gggc HCDR3 (Kabat)SEQ ID No.: 60 ggcttcgccatccggtactacggcttcgactac HCDR1 (Chothia)SEQ ID No.: 61 ggcttcaccgtgtccgactac HCDR2 (Chothia) SEQ ID No.: 62ggcggcgtgggcgagggc HCDR3 (Chothia) SEQ ID No.: 63ggcttcgccatccggtactacagcttcgactac LCDR1 (Kabat & Chothia) SEQ ID No.: 64tccggcgacaagctgggcgataagtacgcctac LCDR2 (Kabat & Chothia) SEQ ID No.: 65caggactccaagcggccctcc LCDR3 (Kabat & SEQ ID No.: 66caggtgttcaccttccccctggtcaccacc Chothia) VL (DNA) SEQ ID No.: 67tcctacgagctgacccagcccccctccgtgtccgtgtctcctggccagaccgcctccatcacctgttccggcgacaagctgggcgataagtacgcctactggtatcagcagaagcccggccagtcccccgtgctggtcatctaccaggactccaagcggccctccggcatccctgagcggttctccggctccaactccggcaacaccgccaccctgaccatctccggcacccaggccgaggacgaggccgactactactgccaggtgttcaccttccccctggtcaccaccgtgttcggcggaggcaccaagctgaccgtgctgggccag VH (DNA) SEQ ID No.: 68gaggtgcagctgctggaatccggcggaggactggtgcagcctggcggctccctgagactgtcttgcgccgcctccggcttcaccgtgtccgactacgctatgcactgggtccgacaggcccctggcaagggcctggaatgggtgtcctatatcgacgacgtgagcgagggcacccagtacactgaatctgtgaagggccggttcaccatctcccgggacaactccaagaacaccctgtacctgcagatgaactccctgcgggccgaggacaccgccgtgtactactgtgccagaggcttcgccatccggtactacggcttcgactactggggccaggacaccctggtcaccgtgtctagc Light chain SEQ ID No.: 69tcctacgagctgacccagcccccctccgtgtccgtgtctcctggccaga (DNA)ccgcctccatcacctgttccggcgacaagctgagcaataagtacgcctactggtatcagcagaagcccggccagtcccccgtgctggtcatctaccaggactccaagcggccctccggcatccctgagcggttctccggctccaactccggcaacaccgccaccctgaccatctccggcacccaggccgaggacgaggccgactactactgccaggtgttcaccttccccctggtcaccaccgtgttcggcggaggcaccaagctgaccgtgctgggccagcctaaggccgctccctccgtgaccctgttccccccatcctccgaggaactgcaggccaacaaagccaccctggtctgcctgatctccaacttctaccctggcgccgtgaccgtggcctggaaggccgacagctctcctgtgaaggccggcgtggaaaccaccaccccctccaagcagtccaacaacaaatacgccgcctcctcctacctgtccctgacccccgagcagtggaagtcccaccggtcctacagctaccagatcacacacaagggctccaccatggaaaaga ccgtggcccctaccgagtgctccHeavy chain SEQ ID No.: 70gaggtgcagctactggaatccggcggaggactggtgcagcctggcg (IgG1, DNA)gctccctgagactgtcttgcgccgcctccggcttcaccgtgtccgactacgctatacactgggtccgacaggcccctggcaagggcctggaatgggtgtcctatatcggcggcgtgggcgagggcacccagtacgctaagtctgtgaaggaccggttcaccatctcccgggacaactccaaaaacaccctgtacctgcagatgaactccctgcgggccgaggacaccgccgtgtactactgtgccagaggcttcgccatccggtactacggcttcgactactggggccagggcaccctggtcaccgtgtctagcgcctccaccaagggcccctccgtgttccctctggccccctccagcaagtccacctctggcggcaccgctgccagggctgcctggtcaaggactacttccccgagcccgtgaccgtgtcctggaactctggcgccctgacctccggcgtgcacaccttccctgccgtgctgcagtcctccggcctgtactccctgtcctccgtcgtgaccgtgccctccagctctctgggcacccagacctacatctgcaacgtgaaccacaagccctccaacaccaaggtggacaagcgggtggaacccaagtcctgcgacaagacccacacctgtcccccctgccctgcccctgaactgctgggcggaccttccgtgttcctgttccccccaaagcccaaggacaccctgatgatctcccggacccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaactccacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgaaaagaccatctccaaagccaagggccagccccgcgagccccaggtgtacacactgccccctagccgggaaaagatgaccaaaaaccaggtgtccctgacctatctggtcaaggacttctacccctccgacattgccgtggaatgggaatccaacggccaacccgagaacaactacaaaaccaccccccctgtgctggactccaacggctcattcttcctgtactccaagctaaccgtggacaaatcccggtggcagcagggcaacgtgttctcctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgtcc ctgagccccggcaag MAB#2HCDR1 (Kabat) SEQ ID No.: 20 SDHYIS HCDR2 (Kabat) SEQ ID No.: 21YISSSGSTTYYAESVKG HCDR3 (Kabat) SEQ ID No.: 22 QSYYFLPYFDVHCDR1 (Chothia) SEQ ID No.: 23 GFTFSDH HCDR2 (Chothia) SEQ ID No.: 24SSSGST HCDR3 (Chothia) SEQ ID No.: 25 QSYYFLPYFDV LCDR1 (Kabat &SEQ ID No.: 26 TGTSSDVGSYNLVS Chothia) LCDR2 (Kabat & SEQ ID No.: 27EGSKRPS Chothia) LCDR3 (Kabat & SEQ ID No.: 28 ASRGSRRVLYV Chothia) VLSEQ ID No.: 29 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQHPGKAPKLMIYEGSKRPSGVSNRFSGSK SGNTASLTISGLQAEDEADYYCASRGSRRVLYVFGGGTKLTVLGQ VH SEQ ID No.: 30 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDHYISWIRQAPGKGLEWVSYISSSGSTTYYAESVKGRF TISRDNAKNSLYLQMNSLRAEDTAVYYCARQSYYFLPYFDVWGQGTLVTVSS VL (DNA) SEQ ID No.: 31cagagcgccctgacccagccagccagcgttagcggtagcccaggccagagcattaccattagctgcaccggcaccagcagcgacgtgggcagctataacctagttagctggtatcagcagcatccggacaaagccccgaaactgatgatctatgaaggcagcaaacgcccgagcggcgttagcaaccgctttagtggcagcaaaagcggcaacaccgccagcctgaccattagcggcctgcaagccgaagacgaagccgattattactgcgcaagtcggggaagccgtcatatgctgtatgtttttggcgacggtaccaaactgaccgat gctgggccag VH (DNA)SEQ ID No.: 32 caggtgcagctgatggaaagcggcggtggcctgatgaaaccaggcggtagcctgcgcctgagctgcgccgccagcggctttacctttagcgatcattacattagctggattcgccaggccccaggcaaaggcctggaatgggttagctatattagcagcagtggcagcaccacctattacgccgagagcgtgaaagaccgctttaccattagccgcgataacgccaaaaacagcctgtatctgcaaatgaacagcctqcgggccgaagataccgccgtgtattattgcgcgcgacaatcctactatttcctgccttatttcgacgtttggggccagggcaccctggttactgtctcgagc HCDR1 (Kabat) SEQ ID No.: 46 agcgatcattacattagcHCDR2 (Kabat) SEQ ID No.: 47tatattagcagcagtggcaaccacctattacgccgagagcgtgaa aggc HCDR3 (Kabat)SEQ ID No.: 48 caatcctactatttcctgccttatttcgacgtt HCDR1 (Chothia)SEQ ID No.: 49 ggctttacctttagcgatcat HCDR2 (Chothia) SEQ ID No.: 50agcagcagtggcagcacc HCDR3 (Chothia) SEQ ID No.: 51caatcctactatttcctgccttatttcgacgtt LCDR1 (Kabat & SEQ ID No.: 52accggcaccagcagcgacgtgggcagctataacctggttagc Chothia) LCDR2 (Kabat &SEQ ID No.: 53 gaaggcagcaaacgcccgagc Chothia) LCDR3 (Kabat &SEQ ID No.: 54 gcaagtcggggaagccgtcgtgtgctgtatgtt Chothia) Light chainSEQ ID No.: 55 QSALTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQHPGKAPKLMIYEGSKRPSGVSNRFSGSK SGNTASLTISGLQAEDEADYYCASRGSRRVLYVFGGGTKLTVLGQPKAAFSVTLFPPSSEELQANKATLV CLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECS Heavy chain SEQ ID No.: 56QVQLVESGGGLVKPGGSLRLSCAASGFTFSDHYI (IgG1)SWIRQAPGKGLEWVSYISSSGSTTYYAESVKGRF TISRDNAKNSLYLQMNSLRAEDTAVYYCARQSYYFLPYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEFKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAFIEKTiSKAKG QFREFQVYTLPPSREEMTKNQVSLTCLVKGFYFSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Light chain SEQ ID No.: 57cagagcgccctgacccagccagccagcgttagcggtagcccaggcc (DNA)agaacattaccattagctacaccggcaccagcaacgacatgggcagctataacctggttagctggtatcagcagcatccgggcaaagccccgaaactgatgatctatgaaggcagcaaacgcccgagcggcgttagcaaccgctttagtggcagcaaaagcggcaacaccgccagcctgaccattagcggcctgcaagccgaaaacgaaaccgattattactgcacaagtcggggaagccgtcgtgtgctgtatgtttttggcggcggtaccaagctgaccgtgctgggccagcccaaagccgcccctagcgtgaccctgttccccccaagcagcgaggaactccaggccaacaaggccaccdcgtgtgcctgatcagcgacttctaccctggcaccgtgaccgtggcctggaaggccgatagcagccctgtgaaggccggcgtggaaaccaccacccccagcaagcagagcaacaacaaatacgccgccagcagctacctgagcctgacccccgagcagtgaaagtcccacagatcctacagctaccagatcacacacgagggcagcaccgtggaaaagaccgtggcccccaccgagtgcag c Heavy chainSEQ ID No.: 71 caggtgcagctggtggaaagcggcggtggcctggtgaaaccaggcg(DNA) (IgG1) gtagcctgcgcctgagctgcgccgccagcggctttacctttagcgatcattacattagctggattcgccaggccccaggcaaaggcctggaatgggttagctatattagcagcaatggcagcaccacctattacgccgagagcgtgaaaggccgctttaccattagccgcgataacgccaaaaacagcctgtatctgcaaatgaacagcctgcgggccgaagataccgccgtgtattattgcgcgcgacaatcctactatttcctgccttatttcgacgtttggggccagggcaccctggttactgtctcgagcgcgtcgaccaaaggccccagcgtgttccctctggcccccagcagcaagagcacctctggcggaacagccgccagggctgcctggtcaaggactacttccccgagcccgtgaccgtgtcctgaaactctggcgccctgaccagcgacgtgcacacctttccaaccgtgctccagagcagcggcctgtacagcctgagcagcgtcgtgaccgtgcccagcagcagcctgggcacccagacctacatctgcaacgtgaaccacaagcccagcaacacaaaggtggacaagcgggtggaacccaagagctgcgacaagacccacacctgtcccccctgccctgcccctgaactgctgggaggcccctccgtgttcctgttccccccaaagcctaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccagaagtgaagtttaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaagccaaaggccagccccgcgagccccaggtgtacacactgccccctagccgggaagagatgaccaagaaccaggtgtccctgacctgcctcgtgaagggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctcattatcctatacagcaagctgaccgtggacaagagccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgactcctaagccccagcaag

WORKING EXAMPLES List of Abbreviations

-   ANOVA analysis of variance-   BSA bovine serum albumin-   BW body weight-   CDR Complementarity determining region-   DLS Dynamic Light Scattering-   DMEM Dulbecco's Modified Eagle Medium-   EC₅₀ 50% effective concentration-   ECD extracellular domain-   ECL electrochemiluminescence-   ELISA enzyme-linked immunosorbent assay-   EtOH Ethanol-   Fab antigen-binding fragment-   FBS Foetal Bovine Serum-   Fc constant fragment-   HPLC High Performance Liquid Chromatography-   i.p. intraperitoneal(ly)-   i.v. intravenous(ly)-   IC₅₀ 50% inhibitory concentration-   IFN-γ Interferon-gamma-   Ig immunoglobulin-   IHC immunohistochemistry-   IL-17R interleukin 17 receptor-   IL-xx interleukin xx-   K_(D) dissociation constant-   MC903 calcipotriol-   MPEK mouse primary keratinocytes-   mRNA messenger ribonucleic acid-   NF-κB nuclear factor kappa B-   p.o. per os, oral(ly)-   PBS phosphate buffered saline-   qPCR quantitative polymerase chain reaction-   qRT-PCR quantitative real-time polymerase chain reaction-   SEM standard error of the mean-   Th2 Type 2 helper T cells

Example 1 Generation of Antigen, Fab Fragments and Antibodies 1.1Antigen Generation and Quality Control

Amino acid sequences of IL-17C from human, cynomolgus monkey and mouse,were aligned.

Without leader sequence, homology of 79% is shared among all threespecies.

Human Cynomolgus Mouse Human 100%  95%  79% Cynomolgus 100%  79% Mouse100%

IL-17C form different species was purchased from different providers orproduced in-house and solubilised, if necessary. Per 100 μg protein 4 μlbiotinylation reagent of the ECL™ biotinylation module were added andincubated for 60 min at room temperature in the dark with gentleagitation. Subsequently biotinylated protein was purified using Zeba™Desalt spin columns and OD280 nm was determined.

Antigens were biotinylated by using the ECL™ biotinylation module (GEHealthcare; #1061918). After biotinlyation the product was purifiedusing Zeba™ Desalt spin columns (Pierce; #89889).

Biotinylated and non-biotinylated mouse, cynomolgus and human IL-17Cwere subjected to a quality control comprising analyses underdenaturing, reducing and denaturing, non-reducing conditions in SDS-PAGEand in native state by High Pressure-Size Exclusion Chromatography(HP-SEC) and Dynamic Light Scattering (DLS).

HP-SEC was performed on a Dionex UltiMate 3000 Titanium HPLC system(Dionex Corporation, Germering, Germany) in combination with WyattminiDAWN Treos and Wyatt Optilab rEX (Wyatt Technology Europe, Dernbach,Germany). For separation a Tosoh TSK-Gel G3000SWxl column was used(Tosoh Bioscience, Stuttgart, Germany). For each sample 15 μg of proteinwas loaded onto the column, separation was performed at a flow rate of0.5 ml/min and recorded analyzing the UV absorption at 280 nm. Therunning buffer was composed of 49 mM NaH₂PO₄, 51 mM Na₂HPO₄, 100 mMK₂SO₄, 0.0005% Tween-80 at pH 6.8.

All DLS experiments were performed using a DynaPro Titan cuvette system(Wyatt Technology Europe, Dernbach, Germany) with protein concentrationsbetween 0.2 and 1.0 mg/ml. In case of precipitation or particleformation, the sample was centrifuged at 10.000 g for 5 minutes prior tothe experiment.

The extracellular domain (ECD) of mouse IL-17 receptor E (UniProtQ8BH06, isoform 1) and human IL-17 receptor E (UniProt Q8NFR9) werecloned in the expression vector pMAX_vk_Fc2_His using Kpnl and EcoRVresulting in C-terminal Fc2_H fusion constructs. Beside the naturalleader (AG00158) a second construct with a Vκ-Leader was generated(AG00159).

Both constructs were transiently expressed in HKB11 cells. The cellsuspension was scaled up three days post transfection and the cellculture supernatant was harvested 6 days post transfection. Aftersterile filtration, the solution was subjected to protein A affinitychromatography. Buffer exchange was performed to PBS and samples weresterile filtered (0.2 μm pore size). Protein concentrations weredetermined by UV-spectrophotometry. Purity of the products was analysedunder denaturing, reducing and denaturing, non-reducing conditions inSDS-PAGE and in native state by HP-SEC and DLS.

1.2. Pannings and Fab/Antibody Generation

For the antibody generation the MorphoSys Ylanthia® library was used toselect Fab fragments against human IL-17C. The MorphoSys Ylanthia®library (Tiller et al. mAbs 5:3, 1-26; May/June (2013) and U.S. Pat. No.8,728,981) is a commercially available phagemid library and employs theCysDisplay® technology for displaying the Fab on the phage surface(Lohning et al., WO2001/05950).

To identify IL-17C—specific antibodies different panning strategies wereused. Each panning strategy comprised at least 3 individual rounds ofpanning against the respective antigens including human IL-17C (SEQ IDNO.: 1) and mouse IL-17C.

The isolated clones identified were maturated, engineered and/orgermlined in order to increase affinity and/or functionality. Thereafterseveral hundred clones were screened and functionality was rigorouslytested in in vitro assays comprising e.g. the evaluation of binding tohuman, cynomolgus monkey and mouse IL-17C via SET, inhibition of bindingof human, cynomolgus monkey and mouse IL-17C to its respective IL-17REand functional inhibition of IL-17C (IL-17RE-driven NF-κB reporter assayin mouse NIH3T3 cells and IL-17C mediated CSF3 expression in mouseprimary keratinocytes (MPEK)).

Finally two preferred lead molecules (MAB #1 and MAB #2) were selectedand are further described in the working examples as outlined below.

Example 2 Affinity Determination in Monovalent Fab and Bivalent IgGFormat

Monovalent Fab and bivalent IgG affinity was determined by SET.Therefore purified Fabs were titrated on human, cynomolgus or mouseIL-17C for determination of KD. Respectively purified IgGs were titratedon human, cynomolgus or mouse IL-17C for EC₅₀ determination.

Solution equilibrium titration (SET) was basically performed asdescribed in the literature (Friquet et al., (1985) J. Immunol. Meth.77: 305-19). In order to improve the sensitivity and accuracy of the SETmethod, it was transferred from classical ELISA to ECL based technology(Haenel et al: (2005) Anal Biochem. 339.1: 182-84).

Respective results for MAB #1 and MAB #2 are shown in Table 2 and Table3 respectively.

Example 3 Characterization of IL-17C Specific Fabs or IgGs for ReceptorInhibition Activity

Purified IL-17C specific Fabs or IgGs, respectively were tested for itscapacity to inhibit the binding of IL-17C to its specific receptorIL-17RE. Therefore MA6000 384-well plates (Meso Scale Discovery, MSD)were coated with 30 μl of mouse IL17RE/Fc chimeric protein at 75 ng/mlin PBS at 4° C. overnight. The next day a serial antibody dilution(concentrations from 0.001 to 100 nM) were pre-incubated for 30 min atRT with an equal volume of biotinylated human/cynomolgus or mouse IL-17Cto determine an IC₅₀ concentration for receptor binding inhibition.After blocking of plates for 1 h with 2.5% BSA in PBST, previouslyformed antibody-ligand complexes were added for 1 h to coated IL17RE/Fcand receptor binding was detected via Streptavidin-ECL using MSD SectorImager.

Both antibodies (MAB #1 and MAB #2) equally inhibited interaction ofhuman/cynomolgus or mouse IL-17C with IL-17RE in Fab and in IgG format.IC₅₀ concentrations in the double-digit pM-range were observed for bothantibodies in IgG format throughout all three clinically relevantspecies. Results are shown in rows 3 and 4 in Table 2 and Table 3respectively.

Example 4 Functional Testing in IL-17C-Driven NF-κB Reporter Assay

Purified IL-17C specific IgGs were further tested for their ability toinhibit the biological activity of human, mouse and cynomolgus IL-17C ina functional cell based assay that monitors the IL-17C driven activationof a NF-κB reporter gene in NIH3T3 cells overexpressing the murineIL-17RE.

NIH3T3 cells were cultured in DMEM supplemented with 10% FBS and 1%Pen/Strep at 37° C., 5% CO₂. For the assay, N1H3T3 cells weretransfected in suspension with total amount of 100 ng DNA (20 ng mouseIL-17RE expression construct, 50 ng NF-κB luciferase reporter constructand 30 ng pBluescript) using the Polyplus jet-PEI transfection agent. Inbrief, the DNA was diluted in 5 μl 150 mM NaCl (per well) and 0.2 μljet-PEI in 8 μl 150 mM NaCl (per well) was prepared. After 5 minutesincubation at room temperature, the JetPEI® solution was added to theDNA solution and further incubated for 20-30 minutes at roomtemperature. NIH3T3 cells were diluted to have ˜40,000 cells in 87 μlmedium. The cells were added to the DNA-JetPEI I® mix (87 μl cells and13 μl DNA-JetPEI I® mix/well) and the final volume was transferred into96 well plates.

After an overnight incubation at 37° C. in a humidified 5% CO₂incubator, the medium was removed and replaced jetPEI® with 90 μl mediumcontaining 5% FBS and 1% Pen/Strep. 10 μl of a serial antibody dilutionmade in DPBS that was pre-incubated for 30 minutes at room temperaturewith an equal volume of purified recombinant IL-17C (either human IL-17C(Novus # NBP1-42910), mouse mIL-17C (R&D Systems #2306-ml-025) orcynomolgus IL-17C (produced in house)), was added to the cells. Thefinal concentration of IL-17C was 0.5 ng/ml.

After incubating the plates at 37° C. in CO₂ incubator, 100 μlSteadyLite Plus (Perkin Elmer) is added followed by readout of theluminescence on the Envision (Perkin Elmer).

Both antibodies effectively reduced NF-κB reporter gene activationmediated by IL-17RE in the presence of human, mouse and cynomolgusIL-17C. Respective results can be found in row 5 of Table 2 and Table 3respectively.

Example 5 IL-17C-Driven Gene Expression in Primary Human Keratinocytes

Keratinocytes endogenously express the IL-17RE and IL-17RA receptors,both of which are needed for functional signaling of IL-17C. Humanprimary keratinocytes derived from healthy individuals and mouse primarykeratinocytes derived from C57BL/6 mice were therefore used to determinethe capacity of MAB #1 IgG1 and MAB #2 IgG1 to inhibit the biologicalactivity of respectively human and mouse IL-17C in a more physiologicalcontext,

NHEK (normal human epidermal keratinocytes) were obtained from Lonza andcultured in Keratinocyte Growth Medium with supplements (KGM-Gold™Bullet kit. Lonza) following manufacturer's protocol. NHEKs that weresub-cultured to and cryopreserved at passage 3 were thawed andimmediately seeded in KGM cell culture medium at 30,000 cells/well in a96 well cell culture plate. After 2 days, the medium was removed andchanged to KGM-Gold w/o hydrocortisone prior to addition of hIL-17C(Novus # NBP1-42910) and hTNFα (Peprotech #300-01A) to finalconcentrations of 10 ng/ml each.

For testing antibodies, the human IL-17C was first pre-incubated for 30minutes at room temperature with an equal volume of a serial dilution ofantibody made in DPBS, Cells were stimulated with recombinant IL-17C(pre-incubated with or without a dilution of antibody) in presence ofTNFα. Co stimulation with IL-17C and TNFα is known to result insynergistic induction of various genes and was shown to be necessary asIL-17C alone has limited effect on the expression of investigated genes.

Cells were cultured for 48 hours and then total RNA was extracted usingRNeasy 96 Kit (Qiagen), reverse transcribed using Taqman® ReverseTranscription Reagents (Applied Biosystems) and the expression ofbeta-defensin 2 DEFB4A (human) or CSF3 (mouse) genes was determined byquantitative polymerase chain reaction (qPCR). In brief, 10 μl PCRreactions were prepared using Taqman® universal PCR master mix/NoAmpErase® UNG and predesigned Assay-on-demand Gene expressionprimer/probe sets for DEF4B or CSF3 (# Hs00823638_m1, all AppliedBiosystems). qPCR was performed on the ViiA7™ Real-Time PCR instrument(Applied Biosystems). Gene expression was normalized to a housekeepinggene either β-actin (Taqman primer set #4310881E) or GAPDH (Taqmanprimer set #4310893E).

Both antibodies (MAB #1 and MAB #2) were shown to effectively reduce 2DEFB4A (human) or CSF3 (mouse) gene expression respectively andconfirmed their ability to neutralize the biological activity of humanIL-17C and also mouse IL-17C (Table 2 and Table 3).

Overview of Functional In Vitro Characterization:

Respective results from in vitro testing are summarized in Table 2 forMAB #1 and in Table 3 for MAB #2. The amino acid and the nucleic acidsequences of the variable regions and the CDRs of those two antibodiesare shown in Table 1. Both antibodies fulfilled respective criteria andwere considered as potential molecules for clinical development.

TABLE 2 Summary in vitro characterization MAB#1 MAB#1 Human MouseCynomolgus IL-17C IL-17C IL-17C SET monovalent K_(D) = 3950 ± K_(D) =28000 ± K_(D) = 22000 ± affinity (Fab) 50 pM 4000 pM 100 pM (n = 2) (n =2) (n = 2) SET apparent EC₅₀ = 19 ± EC₅₀ = 387 ± EC₅₀ = 257 ± affinity(IgG) 6.9 pM 63 pM 59 pM (n = 3) (n = 3) Receptor inhibition IC₅₀ = IC₅₀= IC₅₀ = assay - Fab format 2900 pM 6000 pM 2700 pM Receptor inhibitionIC₅₀ = IC₅₀ = IC₅₀ = assay - IgG format 59 pM 55 pM 44 pM NF-κB reporterIC₅₀ = 31.3 ± IC₅₀ = 47.6 ± IC₅₀ = 12.8 ± assay 12.1 pM 9.4 pM 1.9 pM (n= 3) (n = 3) (n = 3) Keratinocyte IC₅₀ = 319.2 ± IC₅₀ = 112.1 ± n.d.assay 86.3 pM 26. 7 pM (n = 3) (n = 3)

TABLE 3 Summary in vitro characterization MAB#2 MAB#2 Human MouseCynomolgus IL-17C IL-17C IL-17C SET monovalent K_(D) = 37 ± K_(D) = 460± K_(D) = 63 ± affinity (Fab) 17 pM 90 pM 20 pM (n = 2) (n = 2) (n = 2)SET apparent EC₅₀ = 16 ± EC₅₀ = 323 ± NT affinity (IgG) 4 pM 12 pM (n =3) (n = 3) Receptor inhibition IC₅₀ = IC₅₀ = IC₅₀ = assay - Fab format76 pM 150 pM 50 pM Receptor inhibition IC₅₀ = IC₅₀ = IC₅₀ = assay - IgGformat 58 pM 48 pM 57 pM NF-κB reporter IC₅₀ = 18.5 ± IC₅₀ = 64.8 ± IC₅₀= 12.9 ± assay 2.2 pM 8.6 pM 4.5 pM (n = 3) (n = 3) (n = 3) KeratinocyteIC₅₀ = 279.9 ± IC₅₀ = 51.0 ± n.d. assay 161.7 pM 9.0 pM (n = 3) (n = 3)

Example 6 ELISA-Based Cross-Competition Assay

Cross-competition of an anti-IL-17C antibody or another IL-17C bindingagent may be detected by using an ELISA assay according to the followingstandard procedure.

The general principle of the ELISA-assay involves coating of ananti-IL-17C antibody (such as MAB #1 or MAB #2) onto the wells of anELISA plate. An excess amount of a second, potentiallycross-competitive, anti-IL-17C antibody is then added in solution (i.e.not bound to the ELISA plate). Subsequently a limited amount ofIL-17C-Fc is then added to the wells.

The antibody which is coated onto the wells and the antibody in solutionwill compete for binding of the limited number of IL-17C molecules. Theplate is then washed to remove IL-17C molecules that has not bound tothe coated antibody and to also remove the second, solution phaseantibody as well as any complexes formed between the second, solutionphase antibody and IL-17C. The amount of bound IL-17C is then measuredusing an appropriate IL-17C detection reagent. Therefore, IL-17C may befused with a tag, e.g. Fc, Flag, etc. which can be detected via anappropriate tag-specific agent.

An antibody in solution that is cross-competitive to the coated antibodywill be able to cause a decrease in the number of IL-17C molecules thatthe coated antibody can bind relative to the number of IL-17C moleculesthat the coated antibody can bind in the absence of the second, solutionphase antibody.

This assay is described in more detail further below for two antibodiestermed Ab-X and Ab-Y. In the instance where Ab-X is chosen to be theimmobilized antibody, it is coated onto the wells of the ELISA plate,after which the plates are blocked with a suitable blocking solution tominimize non-specific binding of reagents that are subsequently added.An excess amount of Ab-Y is then added to the ELISA plate such that themoles of Ab-Y IL-17C binding sites per well are at least 10 fold higherthan the moles of Ab-X IL-17C binding sites that are used, per well,during the coating of the ELISA plate. IL-17C is added such that themoles of IL-17C added per well were at least 25-fold lower than themoles of Ab-X IL-17C binding sites that are used for coating each well.Following a suitable incubation period, the ELISA plate is washed and adetection reagent specific for the IL-17C antigen is added to measurethe amount of IL-17C molecules specifically bound by the coatedanti-IL-17C antibody (in this case Ab-X). The background signal for theassay is defined as the signal obtained in wells with the coatedantibody (in this case Ab-X), second solution phase antibody (in thiscase Ab-Y), buffer only (i.e. no IL-17C) and detection reagents. Thepositive control signal for the assay is defined as the signal obtainedin wells with the coated antibody (in this case Ab-X), second solutionphase antibody buffer only (i.e. no second solution phase antibody),IL-17C detection reagents. The ELISA assay needs to be run in such amanner so as to have the positive control signal be at least 6 times thebackground signal.

To avoid any artifacts (e.g. significantly different affinities betweenAb-X and Ab-Y for IL-17C) resulting from the choice of which antibody touse as the coating antibody and which to use as the second (competitor)antibody, the cross-blocking assay needs to be run in two formats: 1)format 1 is where Ab-X is the antibody that is coated onto the ELISAplate and Ab-Y is the competitor antibody that is in solution and 2)format 2 is where Ab-Y is the antibody that is coated onto the ELISAplate and Ab-X is the competitor antibody that is in solution.

Example 7 IL-23 Induced Psoriasis-Model in Mice

To examine in vivo efficacy and therapeutic potential, both candidateantibodies were further evaluated in an IL-23 induced psoriasis-model inmice.

The IL-23 induced psoriasis-model in mice was essentially carried out asdescribed by Rizzo H et al. J Immunol (2011) Vol. 186(3) pp. 1495-1502.

In brief, skin lesions were induced in Balb/C mice by intradermalinjection of IL-23 into the ears (1 μg) for 4 consecutive days (day 1 today 4). Measurement of gross ear thickness was done daily up to day 5 onwhich the mice were sacrificed. At sacrifice, the pinna ears weresampled and cut longitudinally in 2 halves. One half was fixed informalin for in depth histological analysis of epidermal/dermalthickness of ear skin. The second half was immersed in RNAlater forquantitative reverse-transcription polymerase chain reaction (qRT-PCR)analysis of mRNA expression levels of disease-relevant IL-17A, IL-22 andIL-1β pro-inflammatory cytokines and LCN2, S100A8 and S100A9anti-microbial proteins. Groups (n=10) of IL-23 injected mice weretreated with the MAB #1 or MAB #2 antibodies which were administeredtwice i.p. at a dose of 10 mg/kg (once 3 days before and once justbefore the first IL-23 intradermal injection).

Each antibody was tested in 2 independent experiments divided over 3different studies. In each study the following control groups (eachn=10) were included:

A control group of mice did not receive daily injections of IL-23 butinstead received daily intradermal injection of the same volume of aBSA/PBS solution. This group was treated with a negative control isotypeantibody MOR03207 (2×10 mg/kg, i.p.).

For each of the studies the gross ear thickness and epidermal thicknesswas followed over time and individual data points per animal were usedto determine the % prevention of the IL-23 mediated thickening. qPCRexpression data were expressed using the Rq (relative quantity) equation(Rq=2−ΔCt where ΔCt=Ct (gene of interest)−Ct (housekeeping gene)) afternormalization to cyclophilin A expression levels used as housekeepinggene. For all measurements, mean±SEM data of groups were compared with aone-way analysis of variance (ANOVA) and Dunnett multiple comparisonpost hoc test using PRISM software. A “p” value of <0.05 was consideredto be statistically significant (*: p<0.05; **: p<0.01; ***: p<0.001;ns: not significant)

In summary, the administration of both candidates IgGs MAB #1 and MAB #2(2×10 mg/kg) ameliorated the IL-23 induced skin inflammation,demonstrating the in vivo efficacy and therapeutic potential of bothantibodies. Both antibodies had similar effects at level of IL-23induced epidermal thickening and a similar impact at level of IL-23induced gene expression. (see Table 4).

TABLE 4 Summary in vivo efficacy in IL-23 model MAB#1 MAB#2 % preventionof Gross ear −34 −6 thickness (mean and Significant in 2 Not significantin 2 significance in 2-3 studies) out of 2 studies out of 2 studies %prevention of epidermal −62 −50 thickness (mean and Significant in 2Significant in 2 significance in 2-3 studies) out of 2 studies out of 2studies Number of disease related nt/3/6 1/6/nt genes significantlyreduced (in each of the 3 studies performed)

Example 8 MC903 Mouse Model of Atopic Dermatitis

The efficacy of the MAB #1 antibody in atopic dermatitis was examined ina non-infectious cutaneous inflammation mouse model of atopic dermatitiswhere topical application of the low-calcemic vitamin D3 analogue MC903(calcipotriol) induces atopic dermatitis like skin lesion characterizedby a red and scaly skin, accompanied by an epidermal hyperplasia anddermal infiltration of various cell types as well as an increase of Th2cytokine in skin and elevated serum IgE (Li M et al. Proc Natl Acad SciUSA (2006) Vol. 103(31) pp. 11736-11741; Li M et al. J Invest Dermatol.(2009) Vol. 129(2). pp. 498-502).

8.1 Animals

BALB/c mice (female, 8-week old) were obtained from Janvier Labs(France). Mice were kept on a 12 hours light/dark cycle (0700-1900).Temperature was maintained at 22° C., and food and water were providedad libitum.

8.2. Experimental Procedures

In order to induce an AD-like response, 2 nmol MC903 (Tocris, dissolvedin ethanol) was topical applied in a volume of 20 μL on both ears ofmice for 5 consecutive days. A non-disease control group received thesame quantity of ethanol (EtOH).

The severity of skin inflammation (erythema and thickening) was observeddaily. Ear thickness was measured with an electronic caliper (Mitutoyo).Inflammation was further assessed using an in vivo imaging technique. Tothat end, Prosense 680 probe (1.6 nmol, Perkin Elmer) was administeredby intraperitoneal route 24 hours before imaging. Imaging was performedwith the Bruker In-vivo Xtreme Imaging System. Images were captured by adeeply cooled 4MP CCD camera (f-stop 1.1, binning 2×2, 5 sec acquisitiontime, Ex 630 nm, Em 700 nm). For anatomical co-registration, areflectance image was taken (f-stop 2.8, 0.175 sec acquisition time).All images were taken with a 190×190 field of view and images wereanalysed using Molecular Imaging Software version 7.1 (Bruker Biospin,Billerica, Mass., USA). For each group, the mean values and standarderror of mean (sem) was calculated using for each mouse the mean valueof left and right ear.

At sacrifice, samples form ear skin were collected and fixed in 4%formaldehyde before embedding in paraffin. 4 μm-thick slices werestained with hematoxylin and eosin (H&E stain) for histomorphometricevaluation of epidermal thickness by image analysis with Sisn'Comsoftware (France). Five fields per ear (high power field×20) coveringthe whole ear from top to bottom were measured, and the 5 values wereaveraged per ear and per mice (left/right ear). An additional set oftissue slices were prepared for IHC staining of IL-17C using theanti-IL-17C biotinylated MAB antibody (and biotinylated MOR03207 isotypenegative control antibody). Processing and staining was essentially doneas described above.

Ear skin samples were also taken for analysis of cytokine expressionusing qPCR or ELISA. Ear tissue pieces for qPCR gene analysis weresubmerged in RNALater® stabilisation solution (Ambion) and stored at−20° C. Ear skin samples for quantification at protein level wereimmediately snap frozen in liquid N2 and stored at −80° C. For geneexpression analysis, tissue was disrupted and lysed in RNA lysissolution using Precellys homogenisator (microtubes filled with 1.4 mmceramide beads, 3 times 3 cycles of 15 sec at 6000 rpm). Total RNA wasfurther extracted using NucleoSpin® RNA Kit according to manufacturesguidelines (Macherey-Nagel) and 300 ng was reverse-transcribed usingApplied Biosystems™ High-Capacity cDNA Reverse Transcription Kit. 5 μLof 10-fold diluted cDNA was used in real-time quantitative PCR reactionsusing SYBR Green technology with gene-specific primers from Qiagen. qPCRwas performed on the ViiA™ 7 Real-Time PCR System (Applied Biosystems).Gene expression was normalized to the expression of 3 differenthouse-keeping genes (cyclophilin, b-actin and GAPDH) and expressed asrelative mRNA level of specific gene expression as obtained using the2^(−ΔCt) method, with ΔCt=Ctgene−Geomean Ct-value (housekeeping genes).For quantification of expression at protein level, tissues were firstdisrupted and lysed in 250 μL lysis buffer (T-PER™ Tissue ProteinExtraction Reagent (Pierce) supplemented with Protease InhibitorCocktail (Roche) and Halt™ Phosphatase Inhibitor Cocktail (Pierce))using Precellys homogenisator (microtubes filled with 2.8 mm metalbeads, 10 min 14000 rpm at 4° C.). The amount of TSLP in ears wasdetermined using a TSLP mouse DuoSet ELISA kits from R&D System. Theamount was normalized to total protein content in lysate which wasdetermined using Coomassie Protein Assay Reagent (Thermo Fisher) inreference to BSA protein standard. Data were expressed as amount ofcytokine in ear which was calculated using the formula: concentrationcytokine in sample/concentration of protein in sample×total ear proteincontent.

The significance of effect of a treatment on each of the readouts wasassessed with Prism® Software using one-way ANOVA followed by aDunnett's multiple comparison post-hoc test versus the MC903+MOR03207control group with *: p<0.05; **: p<0.01; ***:p<0.001.

8.3. Efficacy of MAB #1 in a Mouse Model of Atopic Dermatitis(Prophylactic)

The efficacy of various doses of MAB #1 in the MC903 atopic dermatitismodel was assessed in a prophylactic setting. In brief, skin lesionswere induced in BALB/c mice by topical administration of 2 nmol MC903(dissolved in ethanol) on both ears for 5 consecutive days; mice weresacrificed at Day 8. MAB #1 was administered i.p. 3 times, i.e. 3 daysbefore, at start of and 4 days after the first MC903 application.Effects on ear swelling, ear inflammation, epidermal hyperplasia, dermalthickness and gene expression were evaluated. A group of mice whichreceived an isotype negative control antibody (MOR03207) served ascomparator. Dexamethasone (5 mg/kg in 0.5% methyl cellulose,administered daily by oral route (p.o.) as of the first day of MC903application) was used as active comparator. Mice were randomly dividedinto equal groups (n=10).

The severity of skin inflammation (erythema and thickening) was followedduring the course of the experiment. The gross ear thickness wasmeasured using a Mitutoyo thickness gage during the course of theexperiment. Inflammation was further assessed at Day 5 using an in vivoimaging technique as described in 8.2).

Ethanol (as vehicle control) had no effect on ears. In contrast,MC903-treated ears became red and swollen. Treatment with MAB #1 atdoses of 2 mg/kg or higher significantly prevented ear thickening. Theeffect of MAB #1 was maximal at a dose of 10 mg/kg and was comparable tothe effect of dexamethasone (FIG. 1). In line with these observations,ear inflammation (assessed by in vivo imaging at Day 5) was clearlyincreased in MC903-treated animals and reduced by MAB #1 withsignificant and near maximal effect observed at a dose of 10 mg/kg (FIG.2).

To confirm the reduction of ear thickness by MAB #1, histologicalsections of ears collected at Day 8 were stained with hematoxylin andeosin for histomorphometric evaluation of epidermal and dermalthickness. Values of five fields per ear covering the whole ear from topto bottom were captured, and averaged per mouse. MAB #1 at doses of 10mg/kg and higher significantly prevented the increase in thickness ofboth epidermal and dermal layer (FIG. 3).

8.3.1 Effect of AB #1 on Gene Expression

To further characterize the effect of MAB #1 in the MC903 atopicdermatitis-like skin inflammation model, the expression of variousatopic dermatitis-relevant genes was analysed at mRNA level by qPCR orat protein level by enzyme-linked immunosorbent assay (ELISA). TSLP andIL-33 protein expression in ears and TARO level in plasma were increasedby MC903 application and significantly inhibited upon treatment with MAB#1 at doses of 10 mg/kg or higher (FIG. 4). A similar inhibitory effectwas observed with MAB #1 on several other genes that were upregulated inMC903-treated ears, like IL-31 (a cytokine linked with itch in atopicdermatitis), the Th2-cytokine IL-4, and other genes that have been shownto be upregulated in human atopic dermatitis, like S100A8/9 and IFN-γ.Vice versa, MAB #1 was shown to prevent the downregulation of FLG2 inMC903-treated ears, which might suggest a potential role of MAB #1 inrestoring barrier function.

8.4 Efficacy of MAB #1 in a Mouse Model of Atopic Dermatitis(Therapeutic)

The efficacy of various doses of MAB #1 in the MC903 atopic dermatitismodel was assessed in a more disease-relevant therapeutic setting. Inbrief, skin lesions were induced in BALB/c mice before the start of anytreatment by topical administration of 2 nmol MC903 (dissolved inethanol) on both ears for 5 consecutive days. MAB #1 was administeredi.p. 4 times, with the first administration at the last day of MC903skin application (Day 5) and following ones at Day 8, 12 and 15. Micewere sacrificed at Day 16. Effects on ear swelling, ear inflammation,epidermal hyperplasia, dermal thickness and gene expression wereevaluated. In addition, effect on influx of immune cells (eosinophils, Tcells and mast cells) was also evaluated. A group of mice which receivedan isotype negative control antibody (MOR03207) served as comparator.Dexamethasone (1 mg/kg in 0.5% methyl cellulose, administered p.o.starting as of the last day of MC903 application at Day 5 andsubsequently from Day 8 to 12 and from Day 15 to 16) was used as activecomparator.

8.4.1 Effect of MAB #1 on Gross Ear Thickness and Inflammation

The gross ear thickness was measured using a Mitutoyo thickness gageduring the course of the experiment. Topical application of MC903 onears elicited a marked increase in ear thickness as of Day 3 as comparedto ears treated with ethanol (as vehicle control for MC903). Diseaseactivity was well induced at Day 5 (i.e. day of first treatment) andcontinued to evolve after (even though MC903 application was stopped) asevident from a continued increase in ear swelling in the group treatedwith the negative control antibody MOR03207 (FIG. 5). Treatment with MAB#1 at doses of 0.4 mg/kg or higher significantly reduced ear thickeningas of Day 12, with the higher doses of MAB #1 having a stronger effectand significantly reducing ear thickness even at earlier time points (asof Day 8 for MAB #1 at 50 mg/kg and as of Day 10 for doses of 10 and 2mg/kg). In line with these observations, ear inflammation as assessed byin vivo imaging (as described in 8.2) at Day 12, was still increased inanimals treated with negative control antibody and significantly reducedby MAB #1 at all doses, with maximal effect observed at dose of 2 mg/kg(FIG. 6).

8.4.2 Effect of MAB #1 on Ear Epidermal/Dermal Thickness

To confirm the reduction of ear thickness by MAB #1, histologicalsections of ears collected at Day 16 were stained with hematoxylin andeosin for histomorphometric evaluation of epidermal and dermalthickness. MAB #1 at doses of 2 mg/kg and higher strongly reduced theincrease in thickness of both epidermal and dermal layer, in line withthe measurements of gross ear thickness (FIG. 7).

8.4.3 Effect of MAB #1 on Dermal Cell Infiltration

To further characterize the effect of MAB #1 on disease processes in theMC903 atopic dermatitis model, we evaluated the effect on cellinfiltrations. More specifically, we assessed the effect on eosinophils,T-lymphocytes and mast cells by immunohistochemistry (IHC) andsubsequent quantification of the area that stained with respectivelyantibodies detecting eosinophil peroxidase, T cell marker CD3 and mastcell tryptases (for details see (Marsais, 2016)). In line with theincreased inflammation and ear thickness, infiltration of eosinophils, Tcells and to lesser extent mast cells was still prominent at Day 16 inears of mice in which disease activity was induced by MC903. Treatmentof MAB #1 reduced the dermal infiltration of all three cell typesexamined (FIG. 8). A significant reduction in number of infiltratedeosinophils and T cells was observed at all MAB #1 doses tested with thehigher dose of 50 mg/kg having the more stronger effect reducing theinflux of these cell types to levels comparable to the effect ofdexamethasone. The effect on mast cell infiltration was in generalweaker but still significant: influx was significantly reduced by MAB #1at the higher doses of 50 and 10 mg/kg.

8.4.4 Effect of MAB #1 on Gene Expression

Expression was analysed on ear skin samples or plasma collected at Day16 either by qPCR for eight disease-relevant genes or by ELISA for TSLPand IL-33 produced in ears and TARO in plasma as described in 8.2.

No significant differential expression could be observed for most of theanalysed genes between EtOH-treated non-disease control mice and mice inwhich disease was induced by application of MC903 for the first 5 days.Only levels of IL-33 protein and IL-4, S100A9 and IFN-γ mRNA expressionlevels were still increased. Increased expression levels for those genes(except IFN-γ) were reduced by MAB #1 treatment as shown in FIG. 9 atall dose levels.

8.5. Results

MAB #1 prevented the generation of an atopic dermatitis-like skininflammation in the MC903 model, with a significant impact on epidermaland dermal thickening, inflammation and type 2 T helper cell (Th2)-likegene expression when dosed prophylactically at 3×10 mg/kgintraperitoneally (i.p.). Significant effects on gross ear thicknesswere already observed in this model at doses of 3×2 mg/kg (i.p.). Alsoin the therapeutic MC903 model MAB #1 improved skin inflammation.Significant therapeutic effects on gross ear thickness, epidermalthickening, inflammation and influx of eosinophils and T cells wereobserved at doses of 4×0.4 mg/kg (i.p.), up to doses of 4×2 to 10 mg/kg(i.p.),

Example 9 Flaky Tail Mouse Model of Atopic Dermatitis

The efficacy of the MAB #1 antibody was evaluated in the Flaky Tailmodel. Flaky Tail mice have a mutation in the Flg and Matt(Matt^(ma/ma)Flg^(ft/ft)) genes resulting in skin barrier dysfunction.These mice spontaneously develop atopy and progressive dermatitischaracterised by a mixed Th2/Th17 inflammatory phenotype and reproducecardinal features of AD in man.

9.1. Animals 8 Experimental Procedures

Flaky tail (Matt^(ma/ma)Flg^(ft/ft)) mice on a congenic C57BL/6Jbackground were used as described in Fallon et al (2009) Nat Genet.41(5): 602-608 and Saunders et al (2013) J Allergy Clin Immunol 132(5):1121-1129. Female Flaky tail mice, 9-10 weeks old, were randomized intofour groups (8 mice per group) and treated for 6 weeks as follows:

-   -   Group I: Isotype negative control antibody (MOR03207) (30 mg/kg,        ip twice weekly×6 weeks)    -   Group II: MAB #1 (3 mg/kg, ip twice weekly×6 weeks)    -   Group III: MAB #1(30 mg/kg, ip twice weekly×6 weeks)    -   Group IV: Dexamethasone 2 mg/kg (ip twice per week×6 weeks) as        active comparator

The severity of AD-like skin inflammation was scored using themacroscopic diagnostic criteria adapted from assessment of skininflammation in the NC/Nga mouse model as described in Saunders et al(2013) J Allergy Olin Immunol 132(5): 1121-1129. In brief, a scoringsystem (0: none; 1: mild; 2: moderate; 3: marked) was applied to thesigns of erythema, excoriation and scaling. The total scores for eachmouse (with the maximum of 9) were calculated from the sum of theindividual scores for each of the three parameters.

The occurrence of eczematous lesions in eyelid skin was monitored at endof the study and blepharitis was scored separately for its severity (0:normal, 1: eyelid erythema and/or edema, 2: eyelid erythema, edema andscaling, 3: eyelid erythema, edema, scaling, erosion). The maximumblepharitis score (mean of both eyes) for each mouse is 3.

9.2. Efficacy of MAB #1 in Spontaneous & Chronic Flaky Tail Mouse Modelof AD

Clinical scoring of skin inflammation shows that Flaky Tail mice hadalready signs of spontaneous eczematous-like dermatitis at start oftreatment which further progressed during the 6-week follow up periodinto an overt dermatitis, in non-treated animals. Treatment with MAB #1reduces progression with significant effect comparable to the effect ofdexamethasone observed at the highest tested dose of 30 mg/kg (FIG. 10).A similar effect of the MAB #1 antibody is observed at the level ofblepharitis at the end of the treatment (FIG. 11).

The invention claimed is:
 1. A nucleic acid encoding an isolatedantibody or antibody fragment specific for IL-17C, wherein said antibodyor antibody fragment comprises (a) a heavy chain complementaritydetermining region (HCDR)1 comprising the amino acid sequence of SEQ IDNO: 7, a HCDR2 region comprising the amino acid sequence of SEQ ID NO:8, a HCDR3 region comprising the amino acid sequence of SEQ ID NO: 9, alight chain complementarity determining region (LCDR)1 region comprisingthe amino acid sequence of SEQ ID NO: 13, a LCDR2 region comprising theamino acid sequence of SEQ ID NO: 14 and a LCDR3 region comprising theamino acid sequence of SEQ ID NO: 15, or (b) a HCDR1 region comprisingthe amino acid sequence of SEQ ID NO: 20, a HCDR2 region comprising theamino acid sequence of SEQ ID NO: 21, a HCDR3 region comprising theamino acid sequence of SEQ ID NO: 22, a LCDR1 region comprising theamino acid sequence of SEQ ID NO: 26, a LCDR2 region comprising theamino acid sequence of SEQ ID NO: 27 and a LCDR3 region comprising theamino acid sequence of SEQ ID NO:
 28. 2. A vector comprising the nucleicacid according to claim
 1. 3. A host cell comprising the vectoraccording to claim
 2. 4. The nucleic acid according to claim 1, whereinsaid encoded antibody or antibody fragment comprises: a) a heavy chainvariable region (V_(H)) comprising the amino acid sequence of SEQ IDNO:17 and a light chain variable region (V_(L)) comprising the aminoacid sequence of SEQ ID NO:16; or b) a V_(H) comprising the amino acidsequence of SEQ ID NO:30 and a V_(L) comprising the amino acid sequenceof SEQ ID NO:29.
 5. A vector comprising the nucleic acid according toclaim
 4. 6. A host cell comprising the vector according to claim
 5. 7.The nucleic acid according to claim 4, wherein said encoded antibody orantibody fragment comprises: a) a heavy chain comprising the amino acidsequence of SEQ ID NO:43 and a light chain comprising the amino acidsequence of SEQ ID NO:42; or b) a heavy chain comprising the amino acidsequence of SEQ ID NO:56 and a light chain comprising the amino acidsequence of SEQ ID NO:55.
 8. A vector comprising the nucleic acidaccording to claim
 7. 9. A host cell comprising the vector according toclaim
 8. 10. A nucleic acid encoding: i) an antibody V_(H) comprising aheavy chain complementarity determining region (HCDR)1 comprising theamino acid sequence of SEQ ID NO:7, a HCDR2 region comprising the aminoacid sequence of SEQ ID NO:8, a HCDR3 region comprising the amino acidsequence of SEQ ID NO:9; ii) an antibody V_(L) comprising a light chaincomplementarity determining region (LCDR)1 region comprising the aminoacid sequence of SEQ ID NO: 13, a LCDR2 region comprising the amino acidsequence of SEQ ID NO:14 and a LCDR3 region comprising the amino acidsequence of SEQ ID NO:15; iii) an antibody V_(H) comprising a HCDR1region comprising the amino acid sequence of SEQ ID NO: 20, a HCDR2region comprising the amino acid sequence of SEQ ID NO: 21, a HCDR3region comprising the amino acid sequence of SEQ ID NO: 22; or iv) anantibody V_(L) comprising a LCDR1 region comprising the amino acidsequence of SEQ ID NO: 26, a LCDR2 region comprising the amino acidsequence of SEQ ID NO: 27 and a LCDR3 region comprising the amino acidsequence of SEQ ID NO:
 28. 11. A vector comprising at least one nucleicacid according to claim
 10. 12. A host cell comprising at least onevector according to claim
 11. 13. A nucleic acid encoding: i) anantibody V_(H) comprising the amino acid sequence of SEQ ID NO:17; ii)an antibody V_(L) comprising the amino acid sequence of SEQ ID NO:16;iii) an antibody V_(H) comprising the amino acid sequence of SEQ IDNO:30; or iv) an antibody V_(L) comprising the amino acid sequence ofSEQ ID NO:29.
 14. A vector comprising at least one nucleic acidaccording to claim
 13. 15. A host cell comprising at least one vectoraccording to claim
 14. 16. The nucleic acid according to claim 13,comprising the nucleic acid sequence set forth as SEQ ID NO:18-19, SEQID NO:44-45, SEQ ID NO:67-70, SEQ ID NO:31-32, SEQ ID NO:57, or SEQ IDNO:71.
 17. A vector comprising at least one nucleic acid according toclaim
 16. 18. A host cell comprising at least one vector according toclaim 17.